The relationship between hypertension and cardiovascular diseases has been consistently observed [1-4], as has the relationship between cardiovascular diseases and hypertensive organ damage, indicated by electrocardiographic (ECG) changes, funduscopic changes, and chronic kidney disease [5]. However, few studies have comprehensively examined such risk factors for stroke. We sought to elucidate the association between risk factors assessed during screening examinations, including markers of hypertensive subclinical organ damage, and the risk of mortality attributed to total stroke and its subtypes, including subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke, in Japanese residents.

The Ibaraki Prefectural Health Study comprised participants aged 40-79 years who underwent a health checkup in 1993 for health education and policymaking purposes [6]. The 93,651 enrolled participants were followed up until 2016. Markers of hypertensive subclinical organ damage were defined as follows: funduscopic changes (Keith-Wagener-Barker classification ≥grade 1), resting ECG ST-T changes diagnosed by well-trained physicians, proteinuria ≥1+, and low estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m². We calculated the population attributable fraction (PAF) to assess the contribution of each risk factor to mortality due to stroke or its subtypes, the hazard ratio (HR) of mortality due to stroke and its subtypes associated with four types of subclinical organ damage, with and without hypertension, and the trend across categories based on the count of subclinical organ damage markers, using Cox proportional hazard models. Detailed methods are provided in Supplementary Methods. The protocol of the Ibaraki Prefectural Health Study was approved by the Ethics Committees of Ibaraki Prefecture (R5-1) and the University of Tsukuba (1628-4). Informed consent was obtained from community representatives to conduct this epidemiological study.

During a 23.1-year median follow-up, there were 3,858 deaths due to total stroke, including 490 from subarachnoid hemorrhage, 905 from intracerebral hemorrhage, and 2,397 from ischemic stroke. Table 1 shows the age-adjusted means and prevalence of baseline characteristics of the patients who died due to stroke and its subtypes and of those who remained stroke-free. Compared with non-cases, those who died from total stroke had a significantly higher prevalence of hypertension, ECG ST-T changes, funduscopic changes, proteinuria, and low eGFR. Similar trends were observed for stroke subtypes. As shown in Table 2 and Supplementary Table 1, atrial fibrillation was strongly associated with the risk of mortality due to total stroke, intracerebral hemorrhage, and ischemic stroke. Current smoking status was significantly associated with mortality due to subarachnoid hemorrhage. In contrast, the PAF of mortality from total stroke was the highest for hypertension (21%). A similar tendency was observed for mortality due to subarachnoid hemorrhage, intracerebral hemorrhage, and ischemic stroke (23%, 18%, and 23%, respectively). Among hypertensive patients (Table 3 and Supplementary Table 2), mortality from total stroke was significantly associated with all four markers when compared with non-hypertensive individuals without subclinical organ damage: multivariable HR (95% confidence interval [CI]) were 2.45 (2.05-2.94) for ECG ST-T changes, 1.82 (1.66-2.00) for funduscopic changes, 1.78 (1.46-2.17) for proteinuria, and 1.78 (1.58-2.01) for low eGFR. Although funduscopic changes, proteinuria, and low eGFR were associated with stroke mortality, even among non-hypertensive individuals, each multivariable HR was lower than that among hypertensive patients. In addition, the number of markers was linearly associated with the risk of mortality from stroke and stroke type in individuals with hypertension. Notably, these results were generally similar when analyzed separately for men and women.

Our results highlight the association of hypertension and subclinical organ damage with mortality due to stroke and its subtypes. The PAF for hypertension of total stroke death (approximately 20%) was consistent with that in the other Asia-Pacific regions [7]. Despite notable regional variations in the impact of hypertension on fatal stroke risk, globally, hypertension was consistently the leading risk factor with the highest PAF for cardiovascular mortality, especially for stroke [1]. It is noteworthy that these markers were also associated with the risk of stroke mortality among non-hypertensive individuals, although the magnitude of association was smaller than that among hypertensive individuals. Our previous study showed that mild hypertensive retinopathy was associated with a higher risk of stroke mortality, regardless of the presence of hypertension [8], and the present study extended these findings by showing that the association was also applicable to other types of subclinical organ damage with a longer follow-up. Subclinical organ damage may reflect masked, borderline, or past hypertension. Thus, screening for these markers may be useful for non-hypertensive individuals to assess the future risk of stroke mortality.

This is the first study to examine the association of hypertension and subclinical organ damage with the risk of mortality due to stroke and its subtypes in Asia. Large-scale cohort settings allowed for the analysis of stroke type and hypertension status. However, this study had several limitations. First, the study population was limited to Japanese individuals; therefore, generalizability should be considered with caution. However, evidence based on the population, including the high incidence of stroke, could provide a reference for other countries affected by stroke epidemics. Second, because participation in health checkups was voluntary, the healthy participant effect was unavoidable. Furthermore, we used data for each risk factor measured only at baseline. During a follow-up period of >20 years, participants characteristics, such as blood pressure, may have changed due to lifestyle modifications or treatment conditions. This may have weakened the association with stroke mortality owing to dilution bias. Finally, owing to its observational nature, this study could not prove that controlling hypertension could prevent stroke. Rather, it highlights the importance of screening for cardiovascular risk factors, including hypertension-related organ damage.

In conclusion, we found significant associations between hypertension, along with markers of subclinical organ damage, and stroke mortality. Screening examinations including hypertensive markers may contribute to the prevention of mortality from any type of stroke in normotensive and hypertensive patients.