Association between physical function and onset of coronary heart disease in a cohort of community-dwelling older populations: The Septuagenarians, Octogenarians, Nonagenarians Investigation with Centenarians study

Objective: Physical function is a strong predictor of the adverse outcomes in older populations. We prospectively examined the association of walking speed and handgrip strength with CHD in the community-dwelling older populations. The study cohort in Japan included 1272 older people free from heart disease at the baseline. Physical function was identied based on walking speed and handgrip strength assessment at the survey site. Any new case of CHD was obtained based on a self-reported doctor's diagnosis. Cox-proportion hazard models were adjusted for covariate factors to examine the CHD risk. Results: During the 7-year follow-up, 45 new cases of CHD were documented. Slow walking speed was strongly associated with CHD risk after adjusting for all confounding factors in the total participants and women (hazard ratio (HR)= 2.53, 95%condence interval (CI), 1.20-5.33, p=0.015, and HR= 4.78, 95% CI,1.07-21.35, p=0.040, respectively), but not in men. Weak grip strength was associated with CHD after age-adjustment (HR= 2.45, 95%CI, 1.03-5.81, p=0.043) only in men. However, after additional multivariate adjustment, the associations were weaker. The results lead to the conclusion that, after multivariate adjustment for coronary heart disease, walking speed is a strong surrogate predictor of the CHD risk among older people.


Introduction
Coronary heart disease (CHD) is the leading cause of premature death worldwide, the incidence increasing by age [1,2]. We now know the traditional risk factor such as hypertension, diabetes, smoking, and so on are the major risk factors of CHD [3][4][5][6]. In recent decade, many studies have shown that improving the physical function can help cardiovascular mortality, and improve well-being in older populations [7][8][9]. Walking speed and grip strength were used as surrogate markers of the physical function and represented the main determinants of physical frailty and sarcopenia. These markers are simple risk strati cation tools, reliable, and valid measures of the functional status. Walking speed and grip strength have been shown to be strong predictors of survival, cardiovascular disease (CVD) mortality, and hospitalizations [10][11][12][13][14][15][16][17]. Nonetheless, studies in the older populations are very limited, and most research used only one method for investigating the outcomes, whereas both methods were used in a few studies. Therefore, investigating whether associations persist after adjusting for both walking speed and grip strength will further help elucidate the potential clinical importance of coronary heart disease within older populations who live in the community.
The study aimed to determine the association of walking speed and grip strength with coronary heart disease in community-dwelling older populations, and we also sex-strati ed subjects because the muscle strength is in uenced by the sex.

Main Text
Research methods Participants were recruited from the SONIC study which is a cohort study of community-dwelling old populations of Japan. The SONIC term comes from Septuagenarians, Octogenarians, Nonagenarians, and Investigation with Centenarians [18]. This study used data from the baseline of the 70, 80, and 90year-old groups in 2010, 2011, and 2012, respectively, until the end of the follow-up in 2018. The subjects eligible for the study had been followed up at least 1 time and were free from heart disease at the baseline. Severe paralysis, stroke, and Parkinson patients were excluded from the study. All participants provided written informed consent to participate on-site prior to starting the survey.

Physical Function
Walking speed and handgrip strength were surrogates of the physical function in this study. Walking speed was assessed at the baseline by measuring the time taken in 2 trials to walk a 2.44-meter course.
Slow walking speed was de ned as an average walking speed < 1 m/s [19] based on two trials of the 2.44-meter walk test. We instructed all participants to walk at a normal speed from a standing start. Grip strength was assessed twice by a hand dynamometer in kilogram units on the dominant side. The average value was used for analysis. Weak grip strength was identi ed according to the Asian working group for sarcopenia consensus (AWGS) as < 26 kg for men and < 18 kg for women [20].

Main Outcome
The outcome of the study was new cases of coronary heart disease (CHD) at the follow-up. Based on the questionnaire, we assessed the history of heart disease depending on whether the participants had been diagnosed by a doctor. The participants were asked about their speci c type of heart disease. CHD was identi ed as a history of myocardial infarction or angina pectoris based on a medical diagnosis selfreport.
Covariate Factors and Other Measurements: We considered covariate factors in the association between physical function and CHD. Diabetes mellitus (DM) was classi ed as fasting blood glucose ≥ 126 mg/dL or random blood glucose testing ≥ 200 mg/dL, Hemoglobin A1c (National Glycohemiglobin Standardization Program (NGSP)) ≥ 6.5%, or taking medication for diabetes [21]. Hypertension (HT) was classi ed as systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or being on antihypertensive treatment [22]. Dyslipidemia (DLP) was classi ed as low-density lipoprotein cholesterol (LDL) ≥ 140 mg/dL, high-density lipoprotein cholesterol (HDL) < 40 mg/dL, triglycerides (TG) ≥ 150 mg/dL, or taking medication for dyslipidemia according to the Japan Atherosclerosis Society (JAS) [23]. Those de nitions were based on the standard for people of all ages in Japanese guidelines. The body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. The smoking experience was divided into two groups: never and ever (current or past smoker) smoking based on a questionnaire.
The carotid ultrasound was used for measure between the intimal-luminal and medial-adventitial interfaces of the carotid artery. The intima-media thickness (IMT) is a space between the two hyperechoic

Results
The analyses were based on 1272 participants who met the inclusion criteria from a total of 2245 participants. During 7-year follow-up, 45 (3.5%) newly patients reported experienced CHD. The prevalence of slow walking was likely to be higher in the CHD group. The prevalence of coronary heart disease was more likely to be higher in men with the 70-year-old group ( Table 1). The characteristics of the participants according to the status of walking speed and grip strength at the baseline are presented in Table 2 for all participants and Additional le 1 Table S1 for sex strati cations. The highest prevalence of slow walking speed and weak grip strength was in the 80-year-old group in all participants and both sexes. Individuals with slow walking speed were more likely to be HT, weak grip strength, lower serum albumin, and higher IMT on considering all participants and sex strati cations. Individuals with weak grip strength were more likely to be those who had slow walking speed, lower serum albumin, lower TCHO, lower BMI, and higher IMT on considering all participants and sex strati cations. The prevalence of physical function status strati ed by age and sex are presented in Additional le 2 gure S1. Those with weak grip strength were more likely to be women in the 70 and 80-year-old groups. Whereas, those with a slow walking speed were more likely to be women in the 70-year-old group.
Table1. Individual characteristics at the baseline according to CHD over 7-year follow-up (N=1272) lines [24]. The procedure was performed by a physician. The average IMT value between left and right sides of the carotid was used for analysis [25,26]. Blood specimens and physical examinations were performed by a physician or registered nurses.
Statistical Analysis: Descriptive statistics were used to examine participant characteristics to determine the status of the physical function according to Japanese society guidelines. The association between the physical function and CHD over the follow-up was assessed using Cox proportional involved 4 models using those variables were revealed on which are traditional risk factors of CHD. Both walking speed and grip strength were simultaneously entered across all models and then adjusted for multivariate factors: model 1 included demographic covariates (age and sex); model 2 was adjusted for vascular disease (HT, DM, DLP) and included model 1; model 3 was adjusted for lifestyle factors (BMI and smoking experience) and included model 1; model 4 (fully adjusted) was adjusted as in model 2 and included model 3. We then investigated whether sex differentiated these associations in models 1 to 4. We used SPSS version 24 software for all analyses. The results are reported with 95% con dence intervals; a two-sided p-value < .05 was considered signi cant. CHD onset over 7-year follow-up

Discussion
The 7-year follow-up study of community-dwelling older populations showed that slow walking at the baseline was a strong predictor of CHD in all populations and older women after adjusting for traditional risk factors of CHD, though not in men. All participants with a walking speed slower than 1 m/s at the baseline had a 2.5 times increased risk of CHD, while those women with a slow walking speed had a 4.8 times increased risk of CHD than those who walk faster. Weak grip strength was signi cantly correlated with CHD in older men after adjustment for age but, after additional multivariate adjustment, the associations were weaker, and no such association was found in women.
We now know that active physical activity is valuable in preventing and reducing the risk of cardiovascular disease mortality [27,28]. Walking speed might re ect time spent on habitual physical activity [29], especially physical activity with moderate intensity, and it is the most common leisure activity and alternative to high-intensity exercise in older populations [30]. Thus, it could affect cardiopulmonary tness and be helpful to release chronic stress and anxiety [31]. This is a novel nding that slow walking is a predictor of CHD in community-dwelling old populations. This supports the results of previous studies, showing that walking speed is linked to cardiovascular disease in general populations [32]. Several studies indicated that people who engage in active physical activity are less likely to show IMT than an inactive group [33,34]. Our results showed that those with a normal physical function (walking speed and grip strength) had a signi cantly lower IMT than those with a poorer physical function. Active physical activity would increase the HDL level, which plays an important role to decrease in ammatory biomarkers associated heart disease [35,36]. Consistent with the current analysis, it has been shown that all participants and women with faster walking have a signi cantly higher HDL than those with slower walking. These are important to explain the bene t of walking speed linked to physical activity to protect against coronary heart disease.
The results showed that weak grip strength was associated with CHD in older men after adjusting for age, but the association was not found after further adjustment, which could be due to the small sample size in men. However, our results revealed that walking speed had a stronger association with CHD than grip strength.
Sex differences in the association between walking speed and CHD in the current study could be due to four reasons. Firstly, the selective survival issue due to cardiovascular mortality in men is higher than women [37], which is a cause of women with CHD live longer than men. Secondly, there is the selection bias issue in frailty. The meta-analysis indicated that older women more tolerate frailty and lower mortality rate than men [38,39]. This is consistent with the results found that the prevalence of slow walking speed in women was increased by advanced age. Thirdly, the onset of CHD was difference between sexes. There were many reports indicated that older men tend to present CHD at a younger age than women [40][41][42]. The current ndings showed a higher prevalence of new-onset CHD in men in the 70-year-old group, while the rate of CHD in women was higher in the 80-year-old group and in the 90-yearold group. Finally, the status of atherosclerosis (IMT) was similar in a group with a slower walking speed and weaker grip strength in both sexes at the baseline. Whereas SBP was slightly higher and HDL was lower in women with slow walking speed. As a result, slow walking speed cannot counter the progression of atherosclerosis in women. These phenomena are likely to in uence the outcome.

Conclusions
Based on the results, walking speed may be a strong surrogate predictor of CHD risk among communitydwelling old populations after multivariate adjustment for traditional risk factors of coronary heart disease. This suggests that the clinical intervention for improving walking speed may lower the CHD risk in community-dwelling old populations.

Limitations
Our study has some limitations, CHD involved a small number of events, leading to insu cient power for subgroup analyses by age group, which would help to more fully understand the mechanism. The data were collected based on self-reports leading to recall bias and the possibility of misclassi cation bias resulting from underreporting of CHD.