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cross sectional image of cerebral stroke

Stroke is the leading cause of premature death and permanent disability in China, accounting for about 35 million cases and 2 million deaths in 2017. Stroke is caused by an occlusion or rupture of blood vessels in the brain. Compared with that in Western populations, a higher proportion of stroke cases in China is haemorrhagic stroke (HS). The very high use of brain imaging for stroke diagnosis in Chinese hospitals, along with additional detailed adjudication of all reported stroke cases in CKB has enabled researchers to reliably classify stroke cases into their pathological types, including ischaemic stroke (IS), intracerebral haemorrhage (ICH), and subarachnoid haemorrhage (SAH) as well as their relevant subtypes (e.g. lacunar and non-lacunar IS). This detailed phenotyping has greatly facilitated research on a wide-range of questions about the aetiology, prognosis, management, risk prediction and prevention of stroke in Chinese adults.

Diagnosis, prognosis and management

Overall 93% of the first stroke cases recorded in CKB had brain imaging for diagnosis and 80% of the reported cases were IS, 16% ICH, 2% SAH, and 2% unspecified type. Based on the adjudication of about 40,000 cases with careful review of the retrieved medical notes so far completed, the overall reporting accuracy for any stroke was 91%, but was higher for ICH and SAH (both 98%) than for IS (79%). For IS, however, the inclusion of silent lacunar infarcts (i.e. imaging detected brain infarcts with no apparent neurological deficits) as IS cases complicated the assessment of accuracy using clinical criteria which requires the presence of a neurological deficit. When imaging and clinical criteria were combined, the diagnostic accuracy of IS cases increased to 93% (Turnbull 2022 In Press).

Following stroke onset, the short- and long-term prognosis varied greatly by different pathological types. For 28-day case-fatality rate, it varied almost 10-fold, being 3%, 47%, 19% and 24% for IS, ICH, SAH and unspecified stroke, respectively. (Lancet Glob Health 2020) At 5 years, the proportion who developed any recurrent stroke were 41% overall (and 41%, 44% and 22% and 40% for IS, ICH, SAH and unspecified stroke types, respectively). For IS most of the recurrent stroke cases were also IS , while for ICH, surprisingly about a half of the recurrent strokes also involved IS and not ICH. At 5 years, a further 10%, 28%, 16% and 15% of those patients died. For silent lacunar infarct, we demonstrated comparable 5-year risks of death (11% vs 14%) and recurrent stroke (38% vs 43%) compared with symptomatic lacunar infarct (Lancet Regional Health Western Pacific - 2021).

The poor prognosis of stroke patients in China may partly reflect inadequate long-term management.

We found that among IS cases, antiplatelet treatments were used by 64%, lipid-lowering medication by 50%, and blood pressure-lowering medication by approximately 42% of all patients, much lower compared with those in Western populations. Similarly, among ICH cases, 53% used blood pressure-lowering medication. An encouraging development is the year-by-year increase in the use of these treatments. Moreover, there appeared diminishing urban and rural disparity in stroke care. Analyses of trends in stroke incidence and care data in CKB indicated that hospitalisation rates for stroke increased by about 5% per year between 2009 and 2016, with greater improvement in lower socioeconomic groups (e.g. rural residents) consistent with health care reform in China (Lancet Glob Health 2020).

Risk prediction, aetiology and prevention

In CKB stroke incidence varied almost 5-fold between the 10 study areas. For risk prediction, we found the conventional Framingham Stroke Risk Profile had good discrimination for total stroke, but substantially underestimated the absolute risks. Novel stroke risk prediction equations generated in CKB that took account of differences in stroke incidence between regions within China greatly enhanced risk prediction of total stroke and major stroke pathological types (Chun et al 2022 [In press]). CKB has developed 10-year risk scores for prediction of ischaemic heart disease, IS and HS, which have different aetiology, prognosis and indications for treatment. Moreover, these novel scores yielded good discrimination of IHD and stroke subtypes in addition to total cardio-vascular disease without including blood lipids. The flexible recalibration methods developed for the different regions in CKB will enable more widespread use of this risk score in other regions of China with population-based health records on stroke and IHD.(Yang  et al 2022 Neurology In Press).

Many blood-related factors (e.g. plasma cholesterol) are associated with stroke risk, but their causal relevance for different stroke pathological types in Chinese adults is not properly explained. CKB demonstrated contrasting, and apparently causal, associations of plasma LDL-cholesterol with risks of IS and ICH. Within the range of 1.5-3.5  mmol/L examined, a 1 mmol/L higher LDL-C was associated with 17% higher risk of IS but 14% lower risk of ICH. Further genetic analyses in CKB showed these contrasting associations are likely causal (Nat Med 2019).

Given the 4-fold higher incidence of IS than ICH, our results demonstrated that lowering LDL-cholesterol is still likely to have net benefit for prevention of overall stroke and cardiovascular disease in China.

For HDL-C, we found no clear relationship with ICH, but a strong inverse association with IS risk. However, the apparently protective association of HDL-C with IS risk did not appear causal based on the analyses in CKB of loss-of-function genetic variants related to HDL-C metabolism (JAMA Cardiol 2018).

Beyond LDL-C and HDL-C, we also assessed the relevance of different lipids, and lipoproteins for stroke types and myocardial infarction (MI), using NMR-based metabolomics. Lipoproteins and lipids showed similar positive associations of very-low, intermediate and low-density lipoproteins with MI and IS, but not with ICH, while glycoprotein acetyls, glucose and docosahexaenoic acid were associated with all three vascular disease outcomes (J Am Coll Cardiol 2018, IJE 2019).

Previous studies found higher blood concentrations of homocysteine were associated with higher risks of stroke and IHD. Supplementation of folic acid can greatly reduce the blood levels of homocysteine but did not appear to reduce the risk of stroke and IHD in Western populations. In China folic acid fortification has not yet been implemented, and mean plasma folate levels are half those in Europe and one-third of those in North America. These facts facilitated the use of genetic studies in CKB for unbiased investigation of the effects of lifelong differences in homocysteine levels on disease outcomes. In CKB, 21% of participants had the TT genotype for MTHFR, a gene strongly affecting homocysteine metabolism, but this varied from 5% to 41% between the ten study regions in CKB. Individuals with TT genotype had a highly significant 13% higher risk of total stroke, 23% higher risk of ICH, and 11% higher risk of IS compared to those with the CC genotype. For IHD and other disease outcomes, we did not find any significant associations. The CKB findings provided strong support for effective folic acid fortification programmes in China and other countries with low folate levels for the prevention of stroke in addition to neural tube defects. 

Impact of research

Research in CKB has generated novel evidence about the diagnosis, causes, risk prediction, and prevention of stroke types in China and beyond. Improved risk prediction equations generated in CKB can help identify those who would derive maximum benefit from blood pressure-lowering and lipid-lowering medication. The new genetic evidence about the causal role of homocysteine in stroke aetiology has informed the design of a new large randomised trial of folic acid supplementation in China for stroke prevention.

In response to the growing burden of chronic diseases, the Chinese government has developed a Healthy China 2030 Plan, with prevention of stroke as a key action priority. Several key CKB findings were incorporated into disease prevention guidelines in China (Glob Health Promot. 2019) and elsewhere. Future research on stroke should discover additional associations of genetic and novel plasma biomarkers with stroke types and their relevant subtypes that may represent targets for new treatments for stroke.