Globally, stroke is the third leading cause of mortality and a major contributor to long-term disability (1). In 2019, it was responsible for 11.6% of global deaths and 5.7% of the total disability-adjusted life-years (DALYs) (1). With the rapidly ageing population and increases in the prevalence of hypertension and diabetes mellitus in China, the burden of stroke is on the rise, posing an enormous challenge to families and the society as a whole (2, 3). Therefore, identifying modifiable risk factors associated with stroke incidence is of great importance in formulating prevention and treatment strategies.

Handgrip strength (HGS) is a convenient, reliable, and inexpensive assessment of upper limb muscle strength, which could reflect the overall muscle capacity and physical fitness (4). Low HGS has been linked to several adverse health outcomes, including cardiovascular disease, cognitive impairment, disability, and mortality (5–7). Based on the evidence, routine implementation of HGS measurement has been recommended in health care and community settings, especially for the ageing population (6). Nevertheless, most of the current research focuses solely on HGS weakness, while its asymmetry was less discussed (8).

Asymmetric HGS has been found to be detrimental to physical health (9–14). For example, a longitudinal analysis using data from the Health and Retirement Study (HRS) has reported that both HGS weakness and asymmetry independently predicted future activity limitations in Americans aged ≥50 years (9). Likewise, HGS asymmetry has also been found to be a significant predictor of neurodegenerative disorders among Chinese adults aged 60 years and over (10). In addition, several studies have demonstrated a combined effect of HGS weakness and asymmetry on health outcomes, showing greater risks of morbidity accumulation (11), reduced cognitive functioning (12), and functional disability (13, 14) in individuals with both weak and asymmetric HGS.

As the largest organ in the body, skeletal muscle is central to whole-body energy metabolism. Declines in skeletal muscle, reflected by HGS weakness, may result in metabolic dysfunctions like impaired glucose uptake and insulin resistance (15). In addition, HGS weakness has been identified as a risk factor to cardiovascular risk factors, including increased levels of blood pressure (BP), cholesterol, and inflammation (16–18). These conditions can subsequently contribute to an elevated risk of stroke (19–21). Therefore, prospective studies have revealed that HGS weakness was significantly associated with increased risk of stroke (5, 22). However, while HGS asymmetry indicates dysfunction of overall strength capacity, its combined impacts with HGS weakness in the development of new-onset stroke is underexplored. In this study, we aimed to investigate the associations of HGS weakness and asymmetry with the risk of incident stroke among Chinese middle-aged and older adults. Our study may contribute to the establishment of a clinical approach that combines HGS weakness and asymmetry for stroke risk stratification and targeted prevention.

Of the 10,966 participants aged 45 years or older, 5,781 (52.7%) were females and the mean age was 59.2 ± 9.4 years at baseline. Figure 2 depicts a histogram of the HGS ratio among participants, showing that the majority (58.7%) had symmetric HGS, i.e., HGS ratio between 0.9 and 1.1. The number of participants with non-weak and symmetric HGS, asymmetric HGS alone, weak HGS alone, and both weak and asymmetric HGS were 5,232 (47.7%), 3,443 (31.4%), 1,205 (11.0%), and 1,086 (9.9%), respectively (Table 1). Compared to participants without HGS weakness or asymmetry, those with both weak and asymmetric HGS were older, more likely to be females, unmarried, less educated, less obese; and they were also more likely to have higher levels of systolic BP and glucose profiles, and with higher prevalence of self-reported chronic diseases, including diabetes mellitus, hypertension, dyslipidemia, and heart diseases.

During 4 years of follow-up, there were 262 (2.39%) new-onset stroke cases. Compared to non-weak HGS group, those with HGS weakness were more likely to develop stroke (2.01% versus 3.84%, p < 0.001) (Table 2). In contrast, the incidence of stroke was comparable between participants with or without asymmetric HGS (2.72% versus 2.16%, p = 0.060). When weakness and asymmetry of HGS were taken into consideration at the same time, we found that participants with both conditions had the highest incidence rate of stroke compared to the other three groups (p < 0.001).

The association of baseline HGS weakness and asymmetry with the risk of new-onset stroke was presented in Table 2. In the crude model, weakness was associated with 1.95 times (95%CI: 1.51–2.51) greater risk of future stroke attack, whereas asymmetry was not significantly associated with the risk of stroke (HR: 1.26, 95%CI: 0.99–1.61). The findings were consistent in fully adjusted models. When HGS weakness and asymmetry were considered at the same time, using non-weak and symmetric HGS as reference, individuals with both weak and asymmetric HGS tended to have elevated risk of stroke (adjusted HR: 1.80, 95%CI: 1.24–2.60) compared to those with weakness alone (adjusted HR: 1.09, 95%CI: 0.80–1.48) or asymmetry alone (adjusted HR: 1.27, 95%CI: 0.86–1.88), albeit the confidence intervals were generally overlapped. Subgroup analysis by age showed similar associations in participants aged ≥60 years, but not in their counterparts who were younger than 60 years (Supplementary Table S1). Consistent results were also found after excluding incident stroke in 2013 CHARLS survey (Supplementary Table S2) or using a different criterion for asymmetric HGS (Supplementary Figure S1).

The present study reported the individual and joint associations of HGS weakness and asymmetry with new-onset stroke among middle-aged and older Chinese in a cohort setting. We demonstrated that individuals with both weak and asymmetric HGS had a tendency of increased risk of new-onset stroke, compared to those with normal HGS, or with either weak or asymmetric HGS alone. Our findings highlighted the importance of examining HGS asymmetry alongside its weakness to improve the risk-stratification and target prevention of stroke.

The significant association between HGS weakness and incident stroke has been demonstrated by several previous studies (5, 22, 38). For example, the Prospective Urban Rural Epidemiology (PURE) study with data from 17 countries has reported a 9% increased risk of incident stroke associated with every 5 kg reduction in HGS (5). A cohort study of over 280,000 participants from UK biobank has also revealed that weak HGS was linked to a higher hazard for both ischemic and hemorrhagic stroke (38). Moreover, a prospective cohort study using data from CHARLS has reported that weakness and declines in HGS were associated with stroke incidence in middle-aged and older Chinese (22). In accord with above-mentioned studies, we also demonstrated that HGS weakness was associated with increased risk of stroke.

The exact mechanisms underlying the association between HGS weakness and risk of stroke are not fully understood. Skeletal muscle is a major organ of energy metabolism, and when muscle mass is reduced, the uptake of glucose is decreased accordingly. This reduction can subsequently lead to insulin resistance (15), a well-established risk factor of stroke (19). Furthermore, previous studies have demonstrated that HGS weakness was associated with increased level of inflammatory factors (18), such as C-reactive protein and interleukin-6, which in turn could contribute to a heightened vulnerability to stroke incidence (20). In addition, weak HGS might be a product of long-term unhealthy lifestyles and imbalanced nutrition (39, 40). These factors are associated with an increased risk of stroke, irrespective of age (41, 42). Therefore, the significant association between HGS weakness and new-onset stroke appears to be physiologically plausible.

Compared to HGS weakness, the association between HGS asymmetry and health outcomes has been underexplored. A cohort analysis using data from CHARLS has demonstrated that individuals with asymmetric HGS had increased hazard of neurodegenerative disorders during the 4 years follow-up, whereas HGS weakness was not an independent contributor to the outcome (10). Another longitudinal study with over 18,000 American adults aged 50 years or above has shown that HGS asymmetry and weakness were independently associated with increased risk of morbidity accumulation, while the odds were even greater in individuals with co-occurrence of the two conditions (11). Similar findings regarding the combined effect of HGS asymmetry and weakness have also been reported on incident functional disabilities (13, 14), low cognitive function (12), and depression (43). Our study further extends the knowledge of previous studies by demonstrating an augmented risk of stroke in individuals with both weak and asymmetric HGS, albeit no significant association was observed when examining the individual association of HGS asymmetry with new-onset stroke. The exact mechanism underlying the increased risk estimates of stroke in participants with both weak and asymmetric HGS remains unclear. Strength asymmetry between limbs might be a precursor of declines in overall strength capacity, and the co-occurrence of HGS weakness and asymmetry might represent a more severe muscle dysfunction than either condition alone (11). This may help explain the exaggerated risk of stroke in participants with both weak and asymmetric HGS. As such, our study further supports the combined assessments of HGS weakness and asymmetry in health screening to identify high-risk individuals for target prevention of stroke.

Subgroup analysis by age further showed that the associations remained consistent in adults aged ≥60 years, while such associations became statistically non-significant in individuals below 60 years. The mechanisms driving this variation are yet to be fully elucidated. In our study sample, younger adults aged <60 years generally achieved higher educational levels. This could potentially render them more perceptive and responsive to weak HGS, subsequently reducing their stroke risk. In addition, middle-aged individuals usually maintain a more active lifestyle compared to their older counterparts. This heightened physical engagement might mitigate the associations between HGS and stroke susceptibility in the younger population. Our research underscores the importance of HGS monitoring and intervention, particularly in the older population.

Our study demonstrated that HGS weakness in combination with its asymmetry was associated with an increased risk of new-onset stroke in Chinese middle-aged and older adults. The risk estimates tended to be larger than that observed in individuals with normal HGS, or those only with weak HGS or asymmetric HGS. Our findings could provide valuable insights into early identification and intervention for stroke development. Targeting individuals with both weak and asymmetric HGS might have substantial benefits in lowering the risk of stroke. However, future randomized controlled trials are needed to confirm the conclusion.

Publicly available datasets were analyzed in this study. This data can be found in a public, open access repository, and can be accessed at China Health and Retirement Longitudinal Study (CHARLS) http://charls.pku.edu.cn/index/en.html. Requests to access the datasets should be directed to https://charls.pku.edu.cn/en/. The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The ethics of CHARLS was approved by the Biomedical Ethics Review Committee of Peking University (IRB approval number: IRB00001052-11015 and IRB00001052-11014) in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in CHARLS. The current study is a secondary data analysis based on the public data of CHARLS, which is exempt from further ethical approval according to relevant regulations.

BC and VG: conceptualization and supervision. VG: data curation. YZ and VG: formal analysis, funding acquisition, and writing – original draft. YZ, WC, BC, JL, and VG: methodology. WC, BC, LL, and VG: validation. YZ, WC, BC, LL, JL, and VG: writing – review and editing. All authors contributed to the article and approved the submitted version.