To examine the prospective association of BPH with subsequent risk of CVD, including heart disease and stroke.
We used data from China Health and Retirement Longitudinal Study of 5242 Chinese men aged 45 years or older. During a follow-up of 7 years, we identified 613 cases of non-fatal CVD, including 417 heart diseases and 254 strokes. Cox proportional hazards models yielded hazard ratios (HRs) relating BPH to CVD, heart disease, and stroke incidence.
Overall, 8.1% of men reported a history of BPH diagnosed by physicians at baseline. As compared with men without a history of BPH, those reporting a history of BPH had an increased risk of developing CVD (multivariable-adjusted HR = 1.43 [1.12, 1.83], heart disease (1.35 [1.00, 1.83]), and stroke (1.50 [1.03, 2.19]). The subgroup analysis by age at baseline (< 60 vs. ≥ 60 years) showed that the associations appeared to be evident among men < 60 years, particularly for CVD (1.82 [1.24, 2.69]) and heart disease (1.72 [1.06, 2.79]). However, interaction tests suggested the associations were not significantly modified by age (P for interaction > 0.10 for all outcomes).
In Chinese men, BPH was associated with higher risks of CVD, heart disease and stroke, particularly among men aged < 60 years.
Benign prostatic hyperplasia (BPH) is a common genitourinary condition in men. It was reported that the prevalence of BPH reached 40% of men aged 40 years, and continued to rise to nearly 80% in men over 70 years . BPH is characterized by a nonmalignant increase in the prostate gland size, often accompanied by lower urinary tract symptoms (LUTS) and bladder outlet obstruction . A meta-analysis showed that moderate to severe LUTS was associated with an increased incidence of major adverse cardiac events . BPH-related LUTS mainly include storage symptoms (urgency, frequency, nocturia and urge urinary incontinence) and/or voiding symptoms (reduced flow and feeling of incomplete emptying) . Previous cross-sectional studies have demonstrated that men with BPH or BPH-related LUTS have a higher prevalence of cardiovascular disease (CVD) risk factors or CVD than the general population. For example, BPH-related LUTS was found to be associated with higher Framingham cardiovascular disease risk score , and systolic blood pressure . The prevalence of coronary artery disease was found to be significantly higher among subjects with BPH than those without BPH . Cross-sectional studies are not able to determine a temporal relationship; however, cohort studies on the association between BPH and the long-term risk of developing CVD were limited and the results were inconclusive. Two studies found that BPH or BPH-related LUTS was associated with a significant higher risk of CVD [8, 9], but another study did not observe such an association .
Therefore, to fill the research gap, we aimed to examine the association between BPH and risk of CVD, heart disease, and stroke in a nationwide prospective cohort study among Chinese population. We also tested whether age (≥ 60 or < 60 years) could modify the association between BPH and risk of CVD.
Materials and methods
Data were from the China Health and Retirement Longitudinal Study (CHARLS), a nationally representative longitudinal survey among Chinese aged 45 years or older. The details of the CHARLS have been previously described . In brief, the participants were recruited from 150 counties of 28 provinces in China by a four-stage probability sampling method. The baseline survey began at 2011 (wave 1) among 17,708 participants (8476 men and 9232 women) with a response rate of 80.5%. Then participants were followed every 2 years through face-to-face personal interviews and physical examinations by trained doctors. The last follow-up survey was conducted in 2018 (wave 4). Because of the study design, we only included men from the baseline survey. Men with a history of heart disease, stroke, or cancer at baseline were excluded (n = 1049). We excluded 811 men without data on history of BPH. We further excluded 1374 men with a body mass index (BMI) < 14 or > 40. Finally, 5242 Chinese men were eligible for this analysis (Fig. 1).
All the participants have completed written informed consent. Ethics approval for CHARLS was obtained from the Biomedical Ethics Review Committee of Peking University (IRB00001052-11015).
Assessment of BPH
Each man was asked whether they have ever been diagnosed with BPH but not malignant prostate tumor at baseline survey. For men who reported a history of BPH, they were further asked when the condition was first diagnosed and whether they were taking any treatment.
Assessment of CVD
The outcomes were the incidence of CVD (heart disease and/or stroke), heart disease, and stroke. Ascertainment of CVD incidence was based on face-to-face computer-assisted personal interviews. At baseline, men were asked by the survey questions of “Have you been diagnosed with heart attack, coronary heart disease, angina, congestive heart failure, or other heart problems by a doctor?” and “Have you been diagnosed with stroke by a doctor?”. Those who answered “yes” were further asked the first time for diagnosis and which treatment was taken (Chinese traditional medicine, Western modern medicine, or other treatments) for each condition. In the following follow-up surveys, the same questions were asked again to confirm the heart disease and stroke cases.
Assessment of covariates
Assessment of demographic factors, disease history, and lifestyles was based on an interviewer-administered questionnaire, including age, education level, living area, marital status, BMI, history of hypertension, history of dyslipidemia, history of diabetes, status of depressive symptoms, smoking status, and drinking status. Body weight and height were measured by trained staff. BMI was calculated as weight/(height*height). Doctor diagnosed history of hypertension, dyslipidemia, and diabetes were based on self-report. Depressive symptoms were identified using the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10). A cut-off value of 10 or higher was defined as significant depressive symptoms .
Distributional differences by BPH status were evaluated using generalized linear regression. The duration of follow-up for each man was calculated from the date of baseline survey to the date of CVD incidence, loss to follow-up, or the last survey, whichever came first. We used the Cox proportional hazards regression to compute the hazard ratios (HRs) with 95% confidence intervals (CIs) of CVD by comparing men reporting no history of BPH with those reporting a history of BPH. The proportional hazards assumption was accessed by using likelihood ratio tests comparing models with and without a multiplicative interaction term between exposure and follow-up duration. We detected no evidence of assumption violations in every model (P > 0.05 for all tests). We adjusted for age in model 1. Model 2 further adjusted for conventional cardiovascular risk factors to prevent distorting the real effect of BPH on the risk of CVD, including education level (primary school or none, middle school, high school, college or higher), living area (urban or rural area), marital status (married, divorced, widow, or unmarried), BMI (quintile), history of hypertension (yes or no), history of kidney disease (yes or no), history of dyslipidemia (yes or no), history of diabetes (yes or no), status of depressive symptoms (yes or no), smoking status (never, former, current smoking), and drinking status (never drinking, former drinking, less than once per month, ≥ once per month). Missing values were treated as separate categories. Collinearity tests between covariates were performed, and all Pearson Correlation Coefficients were < 0.4, indicating no considerable collinearity between covariates. We conducted a pre-defined subgroup analysis by age (≥ 60 or < 60 years) to test whether age could modify the association between BPH and risk of CVD. All analyses were conducted using SAS software Version 9.4. All tests were two-sided and P values < 0.05 were considered statistically significant.
Table 1 shows the age-adjusted baseline characteristics of 5242 men according to history of BPH. Among 5242 men included in this analysis, 424 (8.1%) reported a history of BPH diagnosed by physicians. Compared with men without a history of BPH, those who reported a history of BPH appeared to be a bit older and have a higher BMI. Men with a history of BPH were more likely to be urban residents, have a higher level of education, and have a history of hypertension, dyslipidemia, diabetes, and depressive symptoms, but were less likely to be current smokers or current drinkers.
During a follow-up of 7 years, we identified 613 cases of non-fatal CVD, including 417 heart diseases and 254 strokes. Table 2 shows HRs (95% CIs) of CVD incidence associated with history of BPH. Compared with men without a history of BPH, those reporting a history of BPH had an increased risk of developing CVD (age-adjusted HR = 1.62 [1.27, 2.07]), heart disease (age-adjusted HR = 1.58 [1.17, 2.12]), and stroke (age-adjusted HR = 1.65 [1.14, 2.38]). After further adjustment for covariates including demographic factors, BMI, previous disease history, and lifestyles, the associations were attenuated but remained statistically significant; the multivariable-adjusted HRs (95% CIs) were 1.43 (1.12, 1.83) for CVD, 1.35 (1.00, 1.83) for heart disease, and 1.50 (1.03, 2.19) for stroke.
We next conducted subgroup analysis by age at baseline (age < 60 vs. age ≥ 60). The associations appeared to be evident among men < 60 years, particularly for the outcomes of CVD and heart disease. However, interaction tests suggested the associations were not significantly modified by age (P for interaction > 0.10 for all outcomes).
In this prospective study of Chinese men, we observed that BPH was associated with higher risks of CVD, heart disease and stroke. This association was evident among men aged < 60, particularly for the outcomes of CVD and heart disease, but was non-significant among men aged ≥ 60.
Some prior cross-sectional studies showed that men with BPH or BPH-related LUTS had a higher prevalence of CVD risk factors or CVD than those without these conditions. BPH-related LUTS including urgency of urination, nocturia and high frequency of urination were found to be correlated with the most significant rises in systolic blood pressure (all P < 0.001) . Another study showed that the prevalence of coronary artery disease among 75 subjects with BPH was significantly higher than 75 subjects without BPH (30.7% versus 12.0%, P < 0.05) . However, cohort studies investigating the association of BPH-related LUTS or BPH with long-term risk of CVD had inconsistent results. In line with our study, an European cohort study reported that men with severe LUTS (based on the International Prostate Symptom Score) had an approximately fourfold increased risk of CVD and stroke compared with those with no or mild LUTS (HR: 3.82, 1.32–11.03), though a limiting factor was the small sample size of participants with severe LUTS, with only 1% of the total study population . A five-year cohort study in Taiwan reported a significant association between BPH and risk of incident atrial fibrillation, with an adjusted HR = 1.19 (95% CI, 1.11–1.28) . However, results from the Krimpen study in the Dutch general population showed the multivariable HR for moderate to severe BPH-related LUTS were 1.08 (0.57–2.07) compared with men with no or mild LUTS after a 6-year follow-up for the incidence of CVD . The discrepancy might be attributable to different participant characteristics, BPH measurement, or cardiovascular endpoints.
The potential mechanisms for the association of BPH and risk of CVD might be based on the role of chronic inflammation. It has been well known that androgens and growth factors can stimulate prostatic cell proliferation and the enlargement of prostatic nodules, leading to BPH progression and chronic prostatic inflammation . In turn, the presence of inflammatory infiltrate may create a proinflammatory environment by releasing proinflammatory cytokines (such as tumor necrosis factor: TNF-α) and growth factors (such as Insulin-like growth factor: IGF-1) [14, 15], which plays a common role in the pathogenesis of BPH and CVD . In addition, an overactive sympathetic nervous system in men with BPH could be another possible explanation. It was observed that BPH-related storage and voiding symptoms were enabled to stimulate sympathetic hyperactivity, which was associated with the elevation of blood pressure [4, 17]. For example, nocturia caused by BPH-associated outlet obstruction contributed to the disturbance of sleep maintenance and lower sleep quality, repeated awakening, daytime fatigue, and voiding episode, all of which resulted in higher sympathetic activity and may disturb blood pressure rhythmicity [18, 19]. Furthermore, erectile dysfunction (ED) may have a potential mediating role in the association between BPH and long-term risk of CVD. BPH with enlarged prostate or related LUTS is closely related to the decline of erectile function [20, 21], where ED was found to significantly increase the risk of CVD, coronary heart disease and stroke, independent of conventional cardiovascular risk factors .
Our study is the first study to examine whether age could modify the association between BPH and long-term risk of CVD. Interestingly, the subgroup analysis showed that the risk for CVD appeared to be more evident among men aged < 60 years, whereas a relatively lower point estimate of HR without statistical significance among men aged ≥ 60 years. The prevalence of BPH is age related and increases markedly with age . In addition, the older men were inclined to have a higher risk level of chronic inflammation, hypogonadism, or other chronic diseases, such as insulin resistance, hypertension, or dyslipidemia, all of which might partially offset the detrimental effects of BPH on CVD risk. However, interaction tests suggested the associations were not significantly modified by age and further large-scale investigations are required.
The strengths of our study included a large nationally representative population and a prospective cohort design with a 7-year follow-up. Our results suggested a potential role of BPH for CVD prevention, highlighting the importance of early BPH screening and diagnosis in general population. Also, patients with BPH, especially for the older, should obtain early treatment, incorporate with other healthy lifestyles, to decrease the risk for CVD. However, several limitations should be addressed. First, since the assessments of BPH and outcomes were defined by self-reported doctor diagnosis, measurement errors and misclassification were inevitable. Nevertheless, positive predictive values and comparatively good specificity of self-reported illness have been proved in cohort studies [24, 25]. Also, the BPH status was not measured during the follow-up; thus, misclassifications of BPH status were possible. Second, we were not able to access the severity or specific symptoms of BPH, including prostate specific antigen, International Prostate Symptom Score, urine flow, post-void residual volume, prostate ultrasound values, and prostate surgery which may relate to CVD risk factors in men with BPH . For example, the severe symptomatic BPH cases, such as urine retention can lead to pain and bloating that further cause changes in blood pressure, and heart rhythm abnormalities . Moreover, men who received androgen deprivation therapy, especially those with prostate surgery as well, might have higher five-year risk of cardiovascular death . Third, our study was not able to establish causal relationships because of the nature of observational design. Although we carefully adjusted for conventional risk factors including hypertension, diabetes, and dyslipidemia, residual confounding (such as family history of CVD) cannot be excluded in our study and remained a possible explanation for the observed associations. Fourth, ED might be a potential mediator of the association between BPH and risk of CVD . Such information was not available in the present study.
In conclusion, among Chinese adults, BPH was associated with higher risks of CVD, heart disease and stroke, particularly among men aged < 60 years. Our results suggested a potential role of BPH detection for the CVD risk assessment and early prevention.
Availability of data and materials
The data are publicly available which can be downloaded at http://charls.pku.edu.cn/index/zh-cn.html.
The code is available after request from the authors.
China Health and Retirement Longitudinal Study
Benign prostatic hyperplasia
Lower urinary tract symptoms
Body mass index
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We would like to thank all the participants in the CHARLS study and the National School of Development of Peking University for providing the data.
CHARLS study was supported by the National Institute on Aging of the National Institute of Health (nos. R01-AG037031-01, R01AG037031-03S1, R03-TW008358-01, and R21-AG031372- 01), the Natural Science Foundation of China (nos. 70910107022, and 71130002), and the Knowledge for Change Program at the World Bank (no. 7159234). The sponsors had no roles in study design, data collection, analysis, and interpretation, or manuscript writing, submitting and publication.
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Ethics approval for CHARLS was obtained from the Biomedical Ethics Review Committee of Peking University (IRB00001052-11015).
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Wang, X., Su, Y., Yang, C. et al. Benign prostatic hyperplasia and cardiovascular risk: a prospective study among Chinese men. World J Urol (2021). https://doi.org/10.1007/s00345-021-03817-z
- Benign prostatic hyperplasia
- Cardiovascular disease
- Prospective study