Discussion

In this longitudinal study, we used the data from a nationwide panel survey, the Korean Longitudinal Study of Aging (KLoSA), on individuals over the age of 45 years Our results show that the relative HGS is strongly associated with CVD in both sexes, and the model fit was the best in comparison with the dominant and absolute HGS which defines HGS as a variable in previous studies. We demonstrated that the effect was modestly stronger in the younger age group (45–64 years). In addition, we calculated the optimal cut point of the relative HGS for CVD in this study using the ROC curve and Youden index (men: < 2.52; women: < 1.55). We also demonstrated that muscle weakness, using HGS as determined by applying relative HGS based cut points, was associated with higher ORs for CVD compared to normal HGS, and the associations were consistent between sexes.

The finding of an inverse association between grip strength and CVD is consistent with previous studies. In a prospective cohort study of half a million UK biobank participants, muscle weakness (defined as grip strength < 26 kg for men and < 16 kg for women) was associated with a higher hazard ratio for cardiovascular mortality and CVD in males and females, and several of these relationships had higher hazard ratios in the younger age group(Celis-Morales et al., 2018).

Two recent studies in the Korean and Chinese populations are also consistent with

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our findings. Yi et al.(Yi et al., 2018) performed a cross-sectional study in order to investigate the association between relative HGS and MetS in Korean adults; they used data from 5,014 Korean adults aged ≥ 20 years (2,472 men and 2,542 women) who participated in the Korea National Health and Nutrition Examination Survey (KNHANES) VI (2014–2015). They found that increasing quartiles of relative HGS (defined as absolute HGS divided by BMI) were inversely associated with the risk of MS in both men and women (men: OR = 0.37; 95% CI, 0.30–0.45; Women: OR = 0.19; 95% CI, 0.14–0.27) after adjustment for age, region of residence, smoking status, heavy alcohol consumption, regular exercise, family income, and education level. Similar to this study, Li et al.(Li et al., 2018) demonstrated that the relative HGS (dominant HGS divided by BMI) was associated with a favorable metabolic pro file, as well as a lower risk of preclinical and established stages of metabolic disease.

Moreover, they reported that relative HGS was a more reasonable predictor of metabolic profile and metabolic disease than absolute HGS. In a 2006 study with 927 Taiwanese people aged 53 years and older (510 men and 417 women), data were retrieved from a nationwide representative population-based cohort cross-sectional study. They defined relative HGS as absolute HGS divided by BMI, and demonstrated that in women, it had a significant association with the blood pressure, triglycerides, total cholesterol to high density cholesterol (HDL-C) ratio, HbA1c, uric acid, Framingham risk score in men, HDL-C, fasting glucose, HbA1c, and log hsCRP.

On the other hand, dominant HGS was only associated with log hsCRP in women.

There was no significant association with any cardiovascular biomarkers or FRS in

65 both sexes(Lee et al., 2016b).

However, unlike our study, a number of studies have reported no association between HGS and cardiovascular risk. Indeed, Gubelmann et al. (Gubelmann et al., 2017a) conducted a longitudinal cohort study in a population-based group aged 50 to 75 years from Switzerland in order to assess the prediction of low HGS on incident CV events and overall mortality. Although they reported that low HGS was significantly associated with an increase in incident cardiovascular events by bivariate analysis, the association disappeared after multivariate adjustment. They explained that these results were likely due to the different criteria of HGS applied in each study (they applied the criteria of weak HGS according to frailty criteria [lowest 20%]) (Fried et al., 2001)).

On the other hand, in the study using the data from the National Health and Nutrition Examination Survey (NHANES), a correlation between higher relative muscle strength and a favorable CVD biomarker profiles such as blood pressure, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides and glucose was reported in both men and women(Lawman et al., 2016).

Furthermore, on secondary descriptive analyses of this study, it was found that the absolute HGS increased significantly with increasing weight status, but that relative HGS decreased significantly with increasing weight status. These results are consistent with our findings in that we found that the relative HGS was inversely

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correlated with BMI in both women (r = -0.39, p < 0.001) and men (r = -0.32, p <

0.001), but that the absolute HGS increased significantly with increasing BMI in both women (r = 0.10, p < 0.001) and men (r = 0.069, p = 0.001).

In the present study, we found that the results were significant in both men and women. However, several previous studies have reported differences in the association between HGS and risk of CVDs among men and women. For instance, a study (Yates et al., 2017), that aimed to quantify the association of self-reported walking pace and HGS with all-cause, cardiovascular, and cancer mortality in a UK biobank, reported that HGS was associated with cardiovascular mortality in men only (HR tertile 1 vs. tertile 3 = 1.38; 1.18–1.62). Yates et al. insisted that gender specific analysis was more suitable than considering sex a confounder, since the mean values of HGS for sex-specific tertiles showed little overlap between men and women (women in the highest tertile had a mean [standard deviation] value of 30.4 [3.3] kg;

men in the lowest tertile had a mean value of 30.6 [4.9] kg). On the other hand, a previous study involving 647 elderly people in Korea that aimed to investigate the association between MetS and muscle strength in community-dwelling men and women (≥ 65 years), showed that men in the younger old group (65–74 years) with MetS were at higher risk for muscle weakness than those without metabolic syndrome.

Yang et al. (Yang et al., 2012) hypothesized that the reason for these differences between both sexes may be a decreased testosterone level in men with MetS, and that this may be a possible explanation for muscle weakness in this population. Moreover,

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the Baltimore Longitudinal Study on Aging (Metter et al., 1999) reported that men had greater rates of decline in muscle strength than women, even after accounting for greater initial strength, and that increased age was associated with a greater loss of strength. Janssen et al. (Janssen et al., 2000) also reported that although men have a greater muscle strength than women, men exhibit a greater age-related decline in absolute strength in all muscle groups over time.

Whether the associations between health outcomes and grip strength are consistent across age categories was rarely investigated. Our findings showed that the associations between grip strength and CVD were moderately stronger in younger age groups. A meta-analysis (Cooper et al., 2010) that investigated 53,476 participants from 14 studies, suggested that the association between grip strength and mortality appeared to be weaker in people under 60 years of age compared to older participants. Despite this, the age interaction was not formally tested due to the low number of studies.Another study of 6,850 participants found no association between grip strength and age for mortality, and they reported that it was difficult to investigate owing to the low participant numbers (Strand et al., 2016). A study has shown that grip strength is substantially linked to health effects across a whole age group in the UK biobank population, and that these associations are stronger in the younger age group. However, this study also reported that determining the underlying reasons for these differences in age associations is difficult, and that further work should investigate this(Yates et al., 2017).

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Although the association between grip strength and health outcomes has been thoroughly explored, the clinical value of measuring grip strength in health screening settings was unclear. A longitudinal study (Yates et al., 2017), based on C index change, when using the HGS in an office-based risk score including age, sex, diabetes diagnosed, BMI, systolic blood pressure, and smoking, the prediction ability of cardiovascular risk was improved (cardiovascular mortality: 0.012; incidence of CVD: 0.009). Furthermore, the improvement with the addition of grip strength is similar to that seen when adding high density lipoprotein cholesterol and N-terminal pro b-type natriuretic peptide for a composite outcome of coronary heart disease, stroke, and heart failure to conventional risk factor scores such as age, sex, smoking, systolic blood pressure, history of diabetes, and concentration of total cholesterol (high density lipoprotein: 0.007; pro b-type natriuretic peptide: 0.020). Moreover, a large longitudinal population study (Prospective Urban-Rural Epidemiology (PURE) study)(Leong et al., 2015), demonstrated that HGS was a stronger predictor of all-cause and cardiac mortality than systolic blood pressure.

The underlying mechanism for the relationships between HGS and risk factors for CVD has not been clearly explored. Due to the fact that a number of factors contribute to HGS, the mechanisms underlying the link between the strength of the handle and CVD are difficult to determine. Analysis from the Hertfordshire Cohort Study showed that a higher grip strength is linked to a healthier pattern of eating, and the

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consumption of dietary protein, antioxidant nutrients, vitamin D, and fatty fish (Robinson et al., 2008). A previous study has also shown that subjects who are more physically active and have lower sedentary time have a higher grip strength(Hamer and Stamatakis, 2013). Furthermore, genetic components (Frederiksen et al., 2002), ethnicity, age, sex, height, and socioeconomic status have also been shown to be associated with grip strength (Newman et al., 2003). However, when we approach HGS as a proxy for muscle weakness, the mechanism can be explained. Skeletal muscle is the largest organ in the human body, and allows the level of muscle mass and strength to be maintained; this not only reduces heart demand during daily physical activity, but also counteracts the chronic catabolism(Volaklis et al., 2015).

Decreased muscle mass with aging slows the metabolic rate and reduces calorie consumption since skeletal muscle is also the main tissue of glucose and triglyceride metabolism. This impact is exacerbated by decreased physical activity, which in turn increases the risk of obesity, resistance to insulin, type 2 diabetes, dyslipidemia, and hypertension irrespective of age (Glasgow et al., 2017). Several health organizations, such as the American Heart Association (Williams et al., 2007) and the American College of Sports Medicine (Pescatello et al., 2004), have recommended moderate-intensity resistance training as an adjunct to aerobic exercise programs for preventing and treating hypertension. In a previous meta-analysis, the effect of resistance training on blood pressure was examined (Kelley and Kelley, 2000). They showed decreases of approximately 3 mm Hg for both SBP and DBP in resistance training subjects. Moreover, several observational studies suggested an independent

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protective effect of muscle strength on all-cause and cancer mortality in middle-aged adults (Ruiz et al., 2008), as well as all-cause mortality in men with hypertension (Artero et al., 2011), and in patients with heart failure (Hulsmann et al., 2004). It has also been inversely and independently associated with age-related weight (Mason et al., 2007) and adiposity (Jackson et al., 2010)gains, risk of hypertension in prehypertensive men (Maslow et al., 2010) and the prevalence and incidence of MetS (Wijndaele et al., 2007; Yi et al., 2018) In children and adolescents, higher levels of muscular fitness have been inversely and independently associated with insulin resistance (Benson et al., 2006), and inflammatory proteins(Ruiz et al., 2008).

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Mechanisms by which muscular strength may improve prognosis of CVD(Artero et al., 2012)

 Higher muscular strength levels seem to be associated with:

 Lower total and abdominal adiposity

 Lower weight and adiposity gain

 Healthier levels of MetS components (BP, WC, TGs, glucose, HDL cholesterol) and lower incidence of MetS

 Lower risk of developing HTN (some evidence in prehypertensive individuals)

 Lower insulin resistance, HOMA (evidence in adolescents)

 Lower chronic inflammation (evidence in children, adolescents and elderly people)

Abbreviations: BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein;

HOMA, homeostasis model assessment; HTN, hypertension; MetS, metabolic syndrome; TGs, triglycerides; WC, waist circumference.

Several limitations must be considered when interpreting our findings. First, although this study was investigated through the GEE model, the clustered approaches to analysis, the results may reflect reverse causality and bidirectional relationships when evaluating the connection between grip strength and CVDs. Second, the methods used to characterize HGS vary considerably with regards to the choice of dynamometer or the measurement protocol. Third, since we analyzed secondary data,

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the duration of data, such as current status of smoking and drinking, were not available. Furthermore, the BMI, which is the main variable in this study, can be inaccurate and the potential for biased can be reported since it is calculated using self-reported height and weight. Fourth, this study was conducted on the Korean population, and there are limitations in generalizing the results to other races. Fifth, although the measurement of HGS is a quick and useful method to assess muscle strength, we could not reflect other aspects of muscle strength, such as quadriceps strength, due to a lack of information. Finally, confounding variables that affect HGS in older people over time, such as nutritional state or presence of arthritis in the hand, could not be considered in this analysis due to a lack of data. Nevertheless, this is the first longitudinal design study to evaluate the association between HGS and the development of CVD using relative HGS based cut point and sarcopenia guidelines in Korean middle aged population. Moreover, we used a national representative survey which was conducted by the Ministry of Labor of Korea from 2006, and enrolled participants who were randomly selected by a multistage, stratified probability sampling among community-dwelling Koreans aged ≥ 45 years.

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