The multimorbidity of hypertension and osteoarthritis and relation with sleep quality and hyperlipemia/hyperglycemia in China’s rural population

Hypertension (HTN) and osteoarthritis (OA) are frequent in middle-aged and elderly people, and the co-occurrence of these two diseases is common. However, the pathogenesis of the multimorbidity of both diseases and the relation with sleep quality, hyperlipemia, and hyperglycemia is unclear. We conducted a cross-sectional study to make sense of the multimorbidity of HTN and OA and the relation with sleep quality, hyperlipemia, and hyperglycemia. The relation between sleep quality and OA and its joint effect with hyperlipemia or hyperglycemia was evaluated with logistic regression models. The additive interaction was assessed with the relative excess risk due to interaction (REEI), the attributable proportion (AP), and the synergy index (S). According to this research in a remote rural area, approximately 34.2% of HTN patients are accompanied with OA and 49.1% are suffering poor sleep. Both hyperlipemia/hyperglycemia and sleep quality were related to OA prevalence with crude ORs of 1.43 (95% CI 1.014–2.029) and 1.89 (95% CI 1.411–2.519, P < 0.001) respectively. An observed additive effect was found greater than the sum of the effects of sleep quality and hyperlipemia/hyperglycemia posed on OA prevalence alone. This additive interaction was observed in females (OR = 3.19, 95% CI 1.945–5.237) as well as males ≥ 65 years old (OR = 2.78, 95% CI 1.693–4.557), with RERI, AP, and S significant. Therefore, poor sleep and hyperlipemia/hyperglycemia are associated with OA, and further studies on the additive interaction among females and males ≥ 65 are warranted.


Materials and methods
Study population. This cross-sectional study included HTN patients from Xuan' en county in a remote mountainous area of central China. All participants are local inhabitants over 18 years old and volunteered to participate, and they have no obstacle in communication. HTN was defined as systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, or current use of antihypertensive medication. The sample size was estimated with the average prevalence of hypertension in China with the equation: where α is 0.05, δ is 0.15p, and p is 30%. To compensate for the non-response rate, the sample was increased by 10% with a final sample size of 685. The study followed the guidelines of the Declaration of Helsinki, and ethical approval and informed consent were obtained.
Data collection. The current cross-sectional data were collected from April to July 2018. Data collection took place in two stages: in the first stage, the study collected a broad range of information on sociodemographic characteristics (e.g. sex, age, marital status, monthly income, education level, place of residency), health-related conditions (e.g. BP value, height, weight, waist, hist), and doctor-diagnosed or self-reported OA (yes or no), hyperlipemia, and hyperglycemia. The second stage comprised face-to-face interviews with structured questionnaires to make sense of their sleep quality and compliance with hypertension.
BP values were taken three times using a mercury gauge sphygmomanometer. Consecutive BP measurements were taken at 5-min intervals from the right arm by our investigators, and the average was used for analysis. The information on participants' sleep quality was gathered with the standard Pittsburgh Sleep Quality Index (PSQI). Seven dimensions were used to describe participants' sleep quality, including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, sleep medication, and daytime dysfunction. The total score of the PSQI scale ranges from 0 to 21, with lower scores indicating better sleep quality. Compliance of hypertension was measured using the Compliance of Hypertensive Patients' scale (CHPS), which contained 14 items. Items were evaluated with a 4-point Likert scale, where a higher score indicated a higher level of compliance.
Association between PSQI and osteoarthritis. The association between PSQI and OA is shown in Table 3. Exposure to hyperlipemia/hyperglycemia and poor sleep quality were both associated with the prevalence of OA in unadjusted and adjusted models. For the participants who suffered hyperlipemia or hyperglycemia, the crude OR was 1.43 (95% CI 1.014-2.029, P = 0.042). Results were also significant in adjusted models (for  Table 4 and Fig. 1).
We further conducted a sex-stratification analysis on top of age-stratification, and a positive interaction was noted both in males aged ≥ 65 and females aged ≥ 65. The degree of synergy for males ≥ 65 can be seen in Table 4 Scientific Reports |  Table 4 and Fig. 3).

Discussion
Analysis of the data from Xuan' en area shows a 34.2% prevalence of OA in hypertensive individuals, indicating a not optimistic situation. Approximately 20.2% of HTN patients have hyperlipemia or hyperglycemia, and 49.1% are suffering poor sleep. In addition, poor sleep quality demonstrates a positive correlation with OA, and it also shows an additive effect with hyperlipemia or hyperglycemia among the males ≥ 65 years and females, especially those ≥ 65. This investigation is a preliminary attempt to explore sleep quality and its additive relation with the multimorbidity of HTN and OA in a resource-limited mountainous area, central China. Epidemiological researches reveal that sleep problems are frequent in all populations and more than half of the elderly older than 65 suffer from it due to chronic diseases or external environments 22 . Notably, in this study, poor sleep showed a more pronounced tendency in HTN patients with OA, including subjective sleep, sleep latency, habitual sleep efficiency, sleep disturbances, daytime dysfunction, and total score, even after adjusting for covariates. This was similar to Table 1. Participants' characteristics according to OA status stratification. Md median, IQR interquartile range, SBP systolic blood pressure, DBP diastolic blood pressure, BMI body mass index, WHR waist-to-hip ratio. Significant differences (P < 0.05) are highlighted in bold.

Compliance of Hypertensive Patients Scale score
Intention (M ± SD) 6 (0-8) 6 (4-9) 0.001 5 (0-7) 6 (0-9) < 0.001 Lifestyle (M ± SD) 6 (0-9) 7 (3-9) < 0.001 5 (0-9) 7 (0-9)   23,24 . Besides, the multimorbidity of OA and HTN found here is much higher than China's overall level of 14.00%, according to China Health and Retirement Longitudinal Study 3 . Because Xuan' en is a poverty-stricken area with a large number of young people leaving for urban, complicated and diverse chronic diseases of the elderly as well as low-income level, inadequate health literacy, and the absence of adequate medical services undoubtedly constitute a huge threat to life health and quality. Given that rural elderly is still inferior in physical health to their counterparts in urban areas 25 , more medical resources and fundamental changes are advocated preferential to these regions. Therefore, more economical and convenient screening and referral to primary care is our most urgent concern. Up to now, the bi-directional relation between sleep and OA has been a major point of discussion in publications concerning this domain, but the possible mechanism is not completely clear yet. A previous national study found a U-shape curve between the prevalence of OA and sleep duration with a nadir in the 7-8 h sleep category 26 . A case-control study additionally proved that sleep disorder was associated to a significant extent with higher odds of developing OA 27 . Based on the above ideas, we hypothesized that there would be direct or indirect associations between OA and sleep quality, and verified it in this study. Although accurate causal relation cannot be inferred due to the limitation of a cross-sectional study, it's suggested that HTN patients with OA could be regularly screened for sleep disturbance with PSQI as a way to relieve the shortage of medical services and medicine. PSQI is a generic scale for measuring the quality and patterns of sleep in adults, and it could be of use for the management of OA and HTN patients 28 . It was shown to have strong reliability and validity with a sensitivity of 98.7 and specificity of 84.4 to differentiate sleep disturbances 29 . For the result in our additive interaction analysis, HTN patients aged ≥ 65 years, especially with hyperlipemia or hyperglycemia, are appropriate Table 4. Additive effect of PSQI with hyperlipemia/hyperglycemia on osteoarthritis. 95% CI 95% confidence interval, RERI relative excess risk due to interaction, AP attributable proportion, S synergy index. Significant differences (P < 0.05) are highlighted in bold. Models were adjusted for age, sex, monthly income, education level, occupation, smoking, alcohol intake frequency, tea intake frequency, and duration of hypertension.    www.nature.com/scientificreports/ to use this self-reported instrument to warn of OA development or exacerbation in remote areas. However, to ensure the stability and feasibility of the results, it awaits to be confirmed by further researches. Currently, the interactions between HTN, metabolism, sleep disorders, and OA are intertwined and complicated. The links between them are not fully elucidated, but a longitudinal study illustrated that poor sleep quality is associated with cardiovascular diseases (CVDs), in particular HTN, starting with microvascular dysfunction 30 . Other studies confirmed that increased BP is attributed to the metabolic syndrome-related mechanism due to poor sleep 31,32 . Metabolic syndrome, especially abnormal lipid metabolism, also contributed to the formation and development of OA 14 . All these might provide an idea for explaining a higher prevalence of OA among HTN accompanied by poor sleep quality and hyperlipemia/hyperglycemia in this research. The link between lipid metabolism, sleep quality, and HTN further strengthens the importance of fostering optimal sleep in preventing or ameliorating the development of OA.

Odds ratio (95% CI)
Furthermore, it is novel and attractive in finding a significant additive effect among females after adjusting for age. So far, the only evidence for a gender-age difference has been through several works of literature, the overall prevalence of OA and CVDs (including hypertension, hyperlipemia et al.) was separately higher in females compared to males over the age of 50 33,34 . The explanation for the higher multimorbidity of HTN and OA in females is associated with the estrogen level, as it correspondingly decreased after peak menopausal age 35 . That, plus the fact that females are more vulnerable to poor sleep than males, may explain why the joint effect of HTN, sleep quality, and hyperlipemia/hyperglycemia is more notable in females.
To our knowledge, this is the first study to report the additive interaction between sleep and hyperlipemia/ hyperglycemia linked with OA prevalence. Nonetheless, several limitations should be addressed. Due to the study design of a cross-sectional study, no causal relationship between sleep quality and the prevalence of OA can be inferred. Therefore, it calls for more rigorous designs to identify predictive factors of sleep impairment in OA. Also, the absence of evaluation indexes that include the intensity of pain, quality of life, and condition of medication makes it difficult to clarify disease outcomes and turnover for HTN patients with OA. Because of a few studies and small samples, we are inspired to go into much depth on this topic in the future with more large-scale studies and multi-regional cooperations.

Conclusion
Poor sleep quality is common and troublesome among people with HTN complicated with OA, and it shows a positive correlation with the prevalence of OA. The additive interaction between HTN, hyperlipemia or hyperglycemia, and sleep quality was observed in females and males ≥ 65, but it was complex and not fully elucidated. Further studies on the links are warranted.