Association of Hypertension and Subclinical Organ Damage With Mortality Due to Stroke and Its Subtypes

Article information

J Stroke. 2025;27(1):144-148

Publication date (electronic) : 2025 January 31

doi : https://doi.org/10.5853/jos.2024.01683

Kenichi Ariyada ¹^,², Kazumasa Yamagishi^,²^,³

, Toshimi Sairenchi ²^,⁴, Tomomi Kihara ², Hiroyasu Iso ⁵, Fujiko Irie ⁶

¹Doctoral Program in Medical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan

²Department of Public Health Medicine, Institute of Medicine, and Health Services Research and Development Center, University of Tsukuba, Tsukuba, Japan

³Department of Public Health, Graduate School of Medicine, Juntendo University, Tokyo, Japan

⁴Medical Science of Nursing, Dokkyo Medical University School of Nursing, Mibu, Japan

⁵Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo, Japan

⁶Tsuchiura Public Health Center of Ibaraki Prefectural Government, Tsuchiura, Japan

Correspondence: Kazumasa Yamagishi Department of Public Health Medicine, Institute of Medicine, and Health Services Research and Development Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577 Japan Tel: +81-29-853-2695 E-mail: yamagishi.kazumas.ge@u.tsukuba.ac.jp

Received 2024 May 6; Revised 2024 July 23; Accepted 2024 December 16.

Dear Sir:

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.

Table 1.

Age-adjusted baseline characteristics of participants developing stroke or its subtypes and of participants remaining free of stroke

Table 2.

Hazard ratios and population attributable fractions of total stroke

Table 3.

Hazard ratios of stroke and its subtypes according to the markers of subclinical organ damage and the number of them among hypertensive individuals among hypertensive and nonhypertensive individuals

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.

Supplementary materials

Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2024.01683.

Supplementary Methodsjos-2024-01683-Supplementary-Methods.pdf

Supplementary Table 1.

Hazard ratios and population attributable fractions of stroke subtypes

jos-2024-01683-Supplementary-Table-1.pdf

Supplementary Table 2.

Hazard ratios of stroke subtypes according to the markers of subclinical organ damage and the number of them among hypertensive individuals among hypertensive and nonhypertensive individuals

jos-2024-01683-Supplementary-Table-2.pdf

Notes

Funding statement

This study was supported by the Ibaraki Prefectural Government and Grants-in-Aid from the Ministry of Health, Labour and Welfare, Health and Labour Sciences Research Grants, Japan (H20-Junkankitou [Seishuu]-Ippan-013, H23-Junkankitou [Seishuu]-Ippan-005, H26-Junkankitou [Seisaku]-Ippan-001, H29-Junkankitou [Seishuu]-Ippan-003, JP20FA1002 and JP-23FA1006), and the Japan Society for the Promotion of Science Kakenhi grant numbers JP17H04121 and JP21H03194.

Conflicts of interest

The authors have no financial conflicts of interest.

Author contribution

Conceptualization: KA, KY. Study design: KA, KY. Methodology: KA, KY, TS, HI, FI. Data collection: KY, TS, FI. Investigation: all authors. Statistical analysis: KA. Writing—original draft: KA. Writing—review & editing: KY, TS, TK, HI, FI. Funding acquisition: KY, TS, HI. Approval of final manuscript: all authors.

Acknowledgements

The authors wish to thank the staff of the Ibaraki Prefectural Government for their management and the staff of the Ibaraki Prefectural Health Plaza for their technical assistance. We also thank F. Miyamasu, Medical English Communications Center, University of Tsukuba, for the language revision.

References

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2. Flint AC, Conell C, Ren X, Banki NM, Chan SL, Rao VA, et al. Effect of systolic and diastolic blood pressure on cardiovascular outcomes. N Engl J Med 2019;381:243–251.

3. Fujiyoshi A, Ohkubo T, Miura K, Murakami Y, Nagasawa SY, Okamura T, et al. Blood pressure categories and long-term risk of cardiovascular disease according to age group in Japanese men and women. Hypertens Res 2012;35:947–953.

4. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765–774.

5. Kitamura A, Yamagishi K, Imano H, Kiyama M, Cui R, Ohira T, et al. Impact of hypertension and subclinical organ damage on the incidence of cardiovascular disease among Japanese residents at the population and individual levels—the circulatory risk in communities study (CIRCS). Circ J 2017;81:1022–1028.

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7. Martiniuk AL, Lee CM, Lawes CM, Ueshima H, Suh I, Lam TH, et al. Hypertension: its prevalence and population-attributable fraction for mortality from cardiovascular disease in the Asia-Pacific region. J Hypertens 2007;25:73–79.

8. Sairenchi T, Iso H, Yamagishi K, Irie F, Okubo Y, Gunji J, et al. Mild retinopathy is a risk factor for cardiovascular mortality in Japanese with and without hypertension: the Ibaraki Prefectural health study. Circulation 2011;124:2502–2511.

Article information Continued

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Table 1.

Age-adjusted baseline characteristics of participants developing stroke or its subtypes and of participants remaining free of stroke

	Men					Women
	Total stroke (n=1,620)	Subarachnoid hemorrhage (n=124)	Intracerebral hemorrhage (n=377)	Ischemic stroke (n=1,093)	Noncases (n=30,194)	Total stroke (n=2,238)	Subarachnoid hemorrhage (n=366)	Intracerebral hemorrhage (n=528)	Ischemic stroke (n=1,304)	Noncases (n=59,599)
Age^* (yr)	67.3^§	62.5^‡	65.2^§	68.6^§	60.2	67.9^§	64.5^§	66.2^§	69.4^§	57.7
Systolic BP (mm Hg)	141.3^§	138.7	141.2^‡	141.7^§	136.2	139.7^§	140.1^§	139.4^‡	139.8	131.8
Diastolic BP (mm Hg)	81.6^‡	81.1	82.7^§	81.2	80.9	79.4^†	81.1^§	80.4^§	78.5^‡	77.7
Hypertension (%)	69.5^§	58.9	66.8^‡	71.5^§	54.9	69.5^§	66.7^§	64.8^‡	72.5^§	44.9
Non HDL-C (mg/dL)	136.5^†	135.5	132.8^§	138.2	140.8	155.2^§	153.3^†	151.4^§	157.2^§	151.0
Low (%)	8.3^‡	10.5^‡	10.6^§	7.1	5.9	2.0^‡	2.5	2.1	1.8^‡	2.7
High (%)	17.8	16.1	17.5	18.3	20.4	35.0^§	33.6	30.5^§	37.3^‡	30.2
HDL-C (mg/dL)	53.2	53.2	54.4^‡	52.6	52.4	55.3	55.8	55.4	55.2	56.8
Low HDL-C (%)	18.3	19.4	17.8	18.6	18.7	12.4	11.8	11.4^†	12.8	9.0
Hypertriglyceridemia (%)	10.0	9.7	9.8	10.0	13.6	9.7^‡	9.3	10.4	9.3^‡	9.6
Hyperglycemia (%)	26.7^‡	27.4	26.3	26.5^†	21.9	17.3	11.2^‡	16.5	19.5^‡	12.6
Atrial fibrillation (%)	3.0^§	0.0	2.4^†	3.7^§	1.0	2.2^§	0.6	1.3^†	3.1^§	0.3
BMI (kg/m²)	22.9^†	22.8	22.6^§	22.9	23.3	23.8	23.5^†	23.8	23.8	23.6
Body weight
Over (%)	23.6	25.0	22.0^†	24.1	28.5	34.6	30.6	34.7	35.4	31.4
Under (%)	5.7	4.8	7.7^‡	5.1	4.2	5.5^‡	4.9	4.6	5.9^‡	3.8
Smoking status
Past (%)	26.8^§	17.7^‡	26.0^†	28.2^‡	27.4	0.7	1.1	0.4	0.7	0.7
Current (%)	50.9^§	61.3^‡	54.9^‡	47.9	50.4	4.6^‡	6.8^‡	4.7	3.8	4.8
Drinking status
Past (%)	7.4	8.1	6.6	7.5	5.6	0.3	0.6	0.2	0.3	0.2
Current (%)	61.1	61.3	61.5	60.9	65.6	6.5	6.8^‡	5.1	6.8	9.6
ECG ST-T changes (%)	2.9^‡	1.6	1.3	3.7^§	1.4	4.9^§	4.6^‡	4.0^†	5.1^§	1.8
Funduscopic changes (%)	42.6^§	36.3^†	37.4^‡	44.7^§	26.0	43.1^§	39.1^‡	40.5^‡	45.5^‡	22.8
Proteinuria (%)	4.1	4.8	3.5	4.0	3.3	3.1^‡	3.3	2.7	3.3^†	1.8
Low eGFR (%)	11.4^†	8.1	11.4^†	11.3	5.8	15.6^§	9.3	13.8^†	18.1^‡	5.5

Values are means or prevalence, adjusted for age.

BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; BMI, body mass index; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate.

Unadjusted;

^†

P<0.1;

^‡

P<0.05;

^§

P<0.001 (difference from noncases).

Table 2.

Hazard ratios and population attributable fractions of total stroke

	No. at risk	Person-years	No. of cases	Crude incidence, per 1,000 person-years	Age- and sex-adjusted HR (95% CI)	Multivariable HR (95% CI)^*	PAF (%) (95% CI)
Hypertension	46,010	873,269	2,682	3.1	1.42 (1.32–1.52)	1.45 (1.35–1.55)	21 (17–25)
Non HDL-C
Low	3,559	65,492	179	2.7	1.55 (1.33–1.80)	1.49 (1.28–1.74)	2 (1–2)
High	25,216	502,764	1,071	2.1	0.96 (0.90–1.04)	0.97 (0.90–1.05)	-
Low HDL-C	11,608	222,267	574	2.6	1.12 (1.02–1.22)	1.15 (1.05–1.27)	2 (1–3)
Hypertriglyceridemia	10,167	203,174	379	1.9	0.93 (0.84–1.03)	0.90 (0.81–1.01)	-
Hyperglycemia	14,916	278,868	820	2.9	1.23 (1.14–1.33)	1.19 (1.10–1.29)	3 (2–5)
Atrial fibrillation	565	8,067	99	12.3	3.35 (2.74–4.09)	3.39 (2.77–4.15)	2 (1–2)
Body weight
Over	28,472	572,126	1,158	2.0	1.01 (0.94–1.08)	0.97 (0.90–1.04)	-
Under	3,730	64,479	216	3.3	1.30 (1.13–1.49)	1.31 (1.14–1.51)	1 (1–2)
Smoking status
Past	9,141	168,988	449	2.7	0.94 (0.82–1.07)	0.92 (0.81–1.05)	-
Current	19,005	348,949	927	2.7	1.37 (1.24–1.53)	1.34 (1.21–1.49)	6 (4–8)
Drinking status
Past	1,927	30,727	127	4.1	1.15 (0.95–1.39)	1.09 (0.90–1.32)	-
Current	26,649	512,905	1,136	2.2	1.06 (0.97–1.16)	1.00 (0.91–1.09)	-

PAF was calculated only when the HR with adjustment for age and sex was significant (P<0.05).

HR, hazard ratio; CI, confidence interval; PAF, population attributable fraction; HDL-C, high-density lipoprotein cholesterol; CI, confidence interval.

Adjusted for age, sex, hypertension, low non HDL-C, high non HDL-C, low HDL-C, hypertriglyceridemia, hyperglycemia, atrial fibrillation, body weight, and smoking and drinking status.

Table 3.

Hazard ratios of stroke and its subtypes according to the markers of subclinical organ damage and the number of them among hypertensive individuals among hypertensive and nonhypertensive individuals

	No. at risk	Person-years	No. of cases	Crude incidence, per 1,000 person-years	Age- and sex-adjusted HR (95% CI)	Multivariable HR (95% CI)^*
Nonhypertensive individuals without subclinical organ damage	39,338	820,199	730	0.9	1.00	1.00
Nonhypertensive individuals with
ECG ST-T changes	433	8,055	23	2.9	1.54 (1.02–2.33)	1.51 (1.00–2.28)
Funduscopic changes	6,511	123,399	363	2.9	1.36 (1.20–1.55)	1.36 (1.20–1.54)
Proteinuria	596	11,024	26	2.4	1.64 (1.11–2.42)	1.62 (1.10–2.39)
Low eGFR	1,532	26,037	108	4.1	1.28 (1.05–1.56)	1.26 (1.03–1.54)
Hypertensive individuals with
ECG ST-T changes	1,241	21,278	134	6.3	2.50 (2.09–3.00)	2.45 (2.05–2.94)
Funduscopic changes	16,567	298,931	1,292	4.3	1.78 (1.62–1.95)	1.82 (1.66–2.00)
Proteinuria	1,616	26,419	109	4.1	1.83 (1.50–2.22)	1.78 (1.46–2.17)
Low eGFR	4,055	65,209	426	6.5	1.78 (1.58–2.00)	1.78 (1.58–2.01)
No. of subclinical organ damage markers^†
0	26,066	516,439	1,110	2.1	1.37 (1.24–1.50)	1.41 (1.28–1.55)
1	16,784	307,041	1,233	4.0	1.77 (1.61–1.95)	1.83 (1.66–2.01)
2	2,804	44,812	292	6.5	2.17 (1.89–2.50)	2.21 (1.91–2.55)
3+	356	4,977	47	9.4	3.19 (2.37–4.30)	3.09 (2.29–4.18)
HR for an increase of 1 category number					1.30 (1.23–1.37)	1.29 (1.23–1.37)

HR, hazard ratio; CI, confidence interval; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol.

Adjusted for age, sex, low non HDL-C, high non HDL-C, low HDL-C, hypertriglyceridemia, hyperglycemia, atrial fibrillation, body weight, and smoking and drinking status;

^†

Indicates the number of subclinical organ damage markers with hypertension comprising ECG ST-T changes, funduscopic changes, proteinuria, or low eGFR. Groups with 3 or more markers were included in groups with 2 markers only when they comprised fewer than 10 cases.