Lifetime Risk of Incident Coronary Heart Disease, Stroke, and Cardiovascular Disease: The Japan Public Health Center-Based Prospective Study

Abstract

Aim: The constellation of cardiovascular disease (CVD) risk factors greatly impacts the lifetime risk (LTR) of incident CVD, but the LTR has not been thoroughly evaluated in the Japanese population.

Methods: We conducted a prospective study involving a total of 25,896 individuals 40-69 years old without a history of CVD in 1995 (Cohort I) and 1993-1994 (Cohort II) in Japan. CVD risk factors (blood pressure, non-high-density lipoprotein [HDL] cholesterol levels, smoking status, and glucose concentrations) were used to stratify them by risk. The sex-specific LTR of incident coronary heart disease, stroke, atherosclerotic CVD, and total CVD were estimated for participants 45 years old in the 4 risk categories with the cumulative incidence rate, adjusting for the competing risk of death.

Results: We found apparent differences in the LTR of total CVD according to the risk stratification. Individuals with ≥ 2 of the risk factors of blood pressure ≥ 140/90 mmHg or treated, non-HDL cholesterol level ≥ 170 mg/dL or treated, current smoker, and diabetes had substantially higher adjusted LTRs of CVD than those in other groups, with a LTR of 26.5% (95% confidence interval, 24.0%-29.0%) for men and 15.3% (13.1%-17.5%) for women at 45 years. The LTR of incident stroke was the highest among CVDs, and the presence of hypertension and diabetes mellitus strongly influenced the LTR of total CVD.

Conclusion: The impact of risk accumulation on LTR of CVD was greater in men, and 1 in 4 men with ≥ 2 major risk factors at 45 years of age developed CVD in their lifetime.

Introduction

Lifetime risk (LTR) prediction starting at 20 years old is recommended for maintaining a healthy lifestyle in the 2018 American Heart Association and American College of Cardiology (AHA/ACC) guidelines¹⁾. We must understand the LTR of cardiovascular disease (CVD) to increase motivation for lifestyle modification, particularly in younger individuals, as pathological studies have shown that atherosclerosis begins at a young age and that it is beneficial to remove risk factors for atherosclerosis at an early age^{2, 3)}.

The Japan Atherosclerosis Society documented the use of the absolute risk equation for the primary prevention of atherosclerotic CVD (ASCVD) in its 2022 guideline⁴⁾. According to the guidelines, risk stratification for lipid management is based on an individual’s absolute risk of ASCVD after 10 years⁵⁾. However, it is difficult to fit the absolute risk to young individuals for prevention strategies, as the occurrence of CVD events in young individuals is rare, even in those with an increased risk of CVD.

Japanese individuals have a low incidence of coronary heart disease (CHD) and a high incidence of stroke⁶⁾, a major difference from Caucasian individuals⁷⁾. In Japanese men, stroke incidence is 4 times higher than stroke mortality, and CHD incidence is approximately 2 times higher than CHD mortality⁶⁾. Therefore, the LTR based on mortality rates may be underestimated, and calculations using morbidity rates may instead be more accurate. Many studies in Japanese subjects have estimated the LTR based on mortality^{8, 9)}, with estimates based on morbidity limited^{10, 11)}. Furthermore, there is little available information on the LTR of different types of CVD involving ASCVD, which consists of CHD and large-artery occlusive infarction (so called, “atherothrombotic infarction”), in the Asian population.

The Japan Public Health-based Prospective (JPHC) study followed participants in 11 Japanese communities for 20 years while registering the incidence of first-ever myocardial infarction, stroke, and stroke subtypes. The LTR was calculated using cumulative incidence rates adjusted for the competing risk of death. As the JPHC study was conducted in a general population ≥ 40 years old, it was only possible to estimate LTRs for that age group. In terms of estimating the LTRs for younger individuals, as stated in the AHA/ACC guidelines, it is preferable to do so for those 20–39 years old. However, as the incidence of CVD in Japanese individuals below 40 years old is extremely low^{12, 13)}, the estimation of LTRs from 40 years old could be considered applicable to younger persons as well.

Aim

We investigated the LTRs of first-ever CHD, stroke, ASCVD, and total CVD at 45 years old in individuals stratified by the presence of major risk factors and the cumulative incidence of CVD outcomes over time in a prospective study.

Methods

Study Population

The JPHC study began in 1990 (Cohort I) and 1993-1994 (Cohort II) in 11 public health centers¹⁴⁾. The total study population contained 140,420 residents of Japanese nationality, 40-59 years old (Cohort I) or 40-69 years old (Cohort II).

Participants were asked about their lifestyle 5 and 10 years after the baseline examination. Because non-high-density lipoprotein-cholesterol (non-HDL-C) levels were not available at baseline in Cohort I, we used data from a survey conducted at 5 years (n=45,019) and baseline in Cohort II (n=63,216). After excluding two communities without CVD registration (n=13,735), we selected 26,538 individuals who were available for baseline examinations. Furthermore, we excluded patients with a history of CVD or extreme hypertriglyceridemia (≥ 600 mg/dL)⁴⁾ and ultimately included 25,896 individuals in the analyses.

This study was conducted in accordance with the Declaration of Helsinki, and the study protocol, including the informed consent procedure of the JPHC study, was approved by the Human Ethics Review Committees of the National Cancer Center (approval #2001-021), Faculty of Medicine, Oita University (approval #1523), and each registered hospital.

Measurements

We determined all risk factor profiles from baseline survey data (body mass index [BMI], hypertension, dyslipidemia, diabetes, and smoking status). The BMI (kg/m²) was calculated by dividing the measured weight by the square of the measured height. Blood pressure was measured in the right arm using a standard mercury sphygmomanometer after the patient had been sitting for at least five minutes. Hypertension was defined as a blood pressure ≥ 140/90 mmHg or the use of medication to treat hypertension. Non-HDL-C was defined as the total cholesterol level minus the HDL-C level. Dyslipidemia was defined as a non-HDL-C ≥ 170 mg/dL⁴⁾. Diabetes was defined as fasting (≥ 8 h since the last meal) plasma glucose ≥ 126 mg/dL, non-fasting plasma glucose ≥ 200 mg/dL, or the use of medication to treat diabetes. The concentrations of total cholesterol, HDL-C, and glucose in blood were measured using conventional enzyme methods. A self-administered questionnaire was used to assess baseline smoking habits (current or non-current smokers).

Combinations of risk factors were determined as follows¹⁵⁾: individuals with all optimal risk factors were defined as those who had untreated blood pressure ＜120/80 mmHg, non-HDL-C ＜150 mg/dL, fasting glucose ＜100 mg/dL (non-fasting glucose ＜140 mg/dL), and were not current smokers. Those who had untreated blood pressure of 120-139 mmHg/80-89 mmHg, untreated non-HDL-C levels of 150-169 mg/dL⁴⁾, and/or fasting glucose of 100-125 mg/dL (non-fasting glucose of 140-199 mg/dL) as a prediabetes condition were considered as having ≥ 1 risk factor that was not optimal. Major risk factors included blood pressure ≥ 140/90 mmHg or treated, non-HDL-C levels ≥ 170 mg/dL or treated⁴⁾; fasting glucose ≥ 126 mg/dL (non-fasting ≥ 200 mg/dL) or treated, or current smokers. These individuals were divided into two groups: those with 1 major risk factor and those with ≥ 2 major risk factors.

Follow-Up

The median follow-up period was 15.0 years, spanning from 1995 to the end of 2009 (Cohort I) and from 1993 to 2012 (Cohort II). Person-years were calculated from the entry date to the first endpoint (incident CVD, death, emigration, or loss to follow-up) or the study end date.

Determinants of Incident CVD

The medical records of 78 major hospitals located in communities capable of treating patients with acute myocardial infarction (AMI) and stroke were surveyed systematically for the occurrence of first-ever AMI, sudden cardiac death, and stroke and reviewed to determine the diagnosis. Stroke was confirmed using computed tomography, magnetic resonance imaging, and autopsy. All stroke diagnoses met the criteria of the National Survey of Stroke¹⁶⁾, which requires symptoms related to neurological deficits of sudden or rapid onset lasting at least 24 h or until death. Stroke subtypes included subarachnoid hemorrhaging, intracerebral hemorrhaging, lacunar infarction, large-artery occlusive infarction, embolic infarction, and unclassified stroke¹⁷⁾. Myocardial infarction met the MONICA project criteria, which required typical chest pain and evidence of infarction from an electrocardiogram, cardiac enzymes, and/or autopsy records¹⁸⁾. Sudden cardiac death (SCD) was defined as death due to an unknown cause that occurred within an hour of onset. AMI+SCD was considered as CHD in our study. ASCVD was defined as a CHD or large-artery occlusive infarction.

CVD was defined as the presence of CHD or stroke. If a participant had both CHD and stroke, the event that occurred first was identified as the outcome. Therefore, the sum of the CHD and stroke cases did not equal the total number of CVD cases.

Statistical Analyses

CVD was observed in 853 men (139,257 person-years of follow-up) and 835 women (278,426 person-years of follow-up), which is a sufficient sample size for an analysis. We estimated the sex-specific LTR of CHD, stroke, ASCVD, and total CVD at 45, 55, 65, and 74 years old (entry age) to 85 years old using the practical incidence estimators (PIE) macro, which was developed based on a modified Kaplan-Meier method with a survival analysis applied¹⁹⁾. This method provided 1-year incidence rates for the event of interest, using age as the time scale from entry age to 85 years old. Cumulative incidence rates adjusted for the competing risk of death were calculated according to the risk stratification with one-year incidence rates. We assessed the LTR up to 85 years old because the number of participants over 85 years old was too small for an accurate assessment. The sex-specific LTR and rate ratios (RRs) of total CVD at 45 years old for hypertension, dyslipidemia, diabetes, and smoking status were compared between individuals with and without each risk factor using a z-test. Statistical significance was set at P＜0.05. The SAS software program (version 9.4; SAS Institute, Inc., Cary, NC, USA) was used for all analyses.

Results

We identified 260 individuals with CHD, 1,457 with stroke, 441 with ASCVD, and 1,688 with CVD in our cohort during the follow-up period. Sex-specific means and proportions according to risk stratification are presented in Table 1. The mean age increased with the grade of risk stratification. The mean systolic blood pressure, diastolic blood pressure, and non-HDL cholesterol levels increased with an increase in the number of risk factors. Men and women with hypertension, dyslipidemia, and diabetes were more commonly classified into the group with ≥ 2 major risk factors than into the group with one major risk factor.

Table 1.Population characteristics stratified by risk group

Variable	Men (n=9,098)				Women (n=16,798)
	All Risk Factors Optimal	≥ 1 Risk Factor Not Optimal	1 Major Risk Factor	≥ 2 Major Risk Factors	All Risk Factors Optimal	≥ 1 Risk Factor Not Optimal	1 Major Risk Factor	≥ 2 Major Risk Factors
Number, n	423	1,772	3,998	2,905	2,113	5,013	6,878	2,794
Mean age, years	55.8±7.7	57.3±7.3	57.3±7.5	57.8±7.4	52.3±7.7	55.0±7.6	57.7±7.0	59.2±6.3
Body mass index, kg/m2	22.4±2.6	23.4±2.7	23.6±3.0	24.1±3.0	22.4±2.8	23.3±3.1	24.1±3.3	25.2±3.4
Current smoker, %	―	―	40.0	71.8	―	―	3.7	9.2
Systolic blood pressure, mmHg	109.0±6.7	125.1±8.4	132.9±17.9	142.0±17.5	107.7±7.1	123.9±9.6	135.1±18.1	144.6±16.4
Diastolic blood pressure, mmHg	67.4±6.2	76.4±6.8	80.3±10.8	84.6±10.8	66.1±6.3	74.5±7.1	79.8±10.7	84.1±10.3
Non-HDL-cholesterol, mg/dL	118.3±20.2	130.7±24.2	135.7±32.0	157.6±40.5	121.3±18.2	136.3±22.9	157.6±35.2	187.1±29.4
Hypertension, %	―	―	45.1	80.9	―	―	56.7	93.6
Dyslipidemia, %	―	―	12.6	48.8	―	―	37.9	90.8
Diabetes, %	―	―	2.3	17.3	―	―	1.7	14.6
Outcomes, n (%)
Coronary heart disease	1 (0.2)	11 (0.6)	46 (1.2)	104 (3.6)	3 (0.1)	19 (0.4)	40 (0.6)	36 (1.3)
Stroke	14 (3.3)	87 (4.9)	286 (7.2)	322 (11.1)	44 (2.1)	141 (2.8)	367 (5.3)	196 (7.0)
ASCVD	2 (0.5)	23 (1.3)	86 (2.2)	150 (5.2)	6 (0.3)	36 (0.7)	77 (1.1)	61 (2.2)
Total CVD	15 (3.6)	97 (5.5)	330 (8.3)	411 (14.2)	47 (2.2)	159 (3.2)	401 (5.8)	228 (8.2)

Individuals with optimal risk factors were defined as those who had untreated blood pressure ＜120/80 mmHg, non-HDL-cholesterol ＜150 mg/ dL, fasting glucose ＜100 mg/dL (nonfasting glucose ＜140 mg/dL), and were not current smokers. Those with untreated blood pressure of 120-139/80-89 mmHg, untreated non-HDL-cholesterol of 150-169 mg/dL, and/or fasting glucose of 100-125 mg/dL (nonfasting glucose of 140-199 mg/dL) were considered as having ≥ 1 risk factor not optimal. Individuals with major risk factors included those with blood pressure ≥ 140/90 mmHg or treated, non-HDL-cholesterol ≥ 170 mg/dL or treated, fasting glucose ≥ 126 mg/dL (nonfasting ≥ 200 mg/dL) or treated, or current smokers. They were classified into 2 groups: 1 major risk factor and ≥ 2 major risk factors.

Abbreviations: HDL, high-density lipoprotein; ASCVD, atherosclerotic cardiovascular disease; and CVD, cardiovascular disease.

Fig.1 shows the cumulative incidence rates of total CVD at 45 years old by risk stratification in men and women adjusted for the competing risk of death. The adjusted cumulative incidence in men and women with ≥ 2 major risk factors was significantly higher than that in other groups. The differences in LTR trends among the four groups were larger in men than in women. The LTR of total CVD in women with all optimal risk factors was low, however it gradually increased in individuals by 85 years of age, therefore approximating that in women with ≥ 1 risk factor that was not optimal.

Fig.1. Lifetime risk of total cardiovascular disease in men and women, according to risk stratification at 45 years old

Individuals with optimal risk factors were defined as those who had untreated blood pressure ＜120/80 mmHg, non-HDL-cholesterol ＜150 mg/dL, and fasting glucose ＜100 mg/dL (non-fasting glucose ＜140 mg/dL) and were not current smokers. Those with untreated blood pressure of 120-139/80-89 mmHg, untreated non-HDL-cholesterol of 150-169 mg/dL, and/or fasting glucose of 100-125 mg/dL (non-fasting glucose of 140-199 mg/dL) were considered as having ≥ 1 risk factor not optimal. Individuals with major risk factors included those with blood pressure ≥ 140/90 mmHg or treated, non-HDL-cholesterol ≥ 170 mg/dL or treated, fasting glucose ≥ 126 mg/dL (non-fasting ≥ 200 mg/dL) or treated, or current smokers. These individuals were divided into 2 groups: those with 1 major risk factor or those with ≥ 2 major risk factors.

Table 2 indicates the LTR by CVD type according to risk stratification in men. The LTR of total CVD at 45 years old increased to 26.5% (95% CI, 24.0%-29.0%) in those with ≥ 2 major risk factors. Even if individuals had just 1 major risk factor, their LTR was 16.9% (95% CI, 15.0%-18.8%) at the same age. The LTRs of CHD, stroke, and ASCVD for men at 45 years old were 7.5% (95% CI, 5.8%-9.1%), 20.2% (95% CI, 17.9%-22.4%), and 10.1% (95% CI, 8.3%-11.8%), respectively, for those with ≥ 2 major risk factors. In contrast, that of ASCVD among those with optimal risk factors was 1.4% (95% CI, 0%-3.6%). Among the types of CVD, the occurrence of stroke had the greatest impact on LTR. The LTRs of CVD at 55, 65, and 75 years old were also estimated.

Table 2.Lifetime risk of cardiovascular disease according to risk stratification in men

	All Risk Factors Optimal	≥ 1 Risk Factor Not Optimal	1 Major Risk Factor	≥ 2 Major Risk Factors
	LTR (95% CI), %	LTR (95% CI), %	LTR (95% CI), %	LTR (95% CI), %
Risk at 45 years of age
Coronary heart disease	0.3 (0.0, 1.0)	1.6 (0.4, 2.7)	2.3 (1.6, 3.0)	7.5 (5.8, 9.1)
Stroke	7.1 (3.1, 11.1)	11.0 (8.4, 13.6)	14.6 (12.8, 16.3)	20.2 (17.9, 22.4)
ASCVD	1.4 (0.0, 3.6)	2.9 (1.4, 4.3)	4.4 (3.4, 5.4)	10.1 (8.3, 11.8)
Total CVD	7.4 (3.4, 11.5)	12.6 (9.7, 15.4)	16.9 (15.0, 18.8)	26.5 (24.0, 29.0)
Risk at 55 years of age
Coronary heart disease	0.4 (0.0, 1.1)	1.6 (0.4, 2.8)	2.3 (1.6, 3.1)	5.7 (4.5, 6.9)
Stroke	7.5 (3.3, 11.7)	11.0 (8.4, 13.6)	13.7 (12.0, 15.3)	19.4 (17.2, 21.5)
ASCVD	1.5 (0.0, 3.8)	2.7 (1.3, 4.1)	4.4 (3.4, 5.4)	8.1 (6.7, 9.5)
Total CVD	7.8 (3.6, 12.1)	12.4 (9.6, 15.3)	16.1 (14.2, 17.9)	23.9 (21.6, 26.2)
Risk at 65 years of age
Coronary heart disease	―	1.6 (0.4, 2.9)	2.0 (1.3, 2.8)	4.2 (3.1, 5.3)
Stroke	7.4 (3.1, 11.7)	9.8 (7.2, 12.5)	12.2 (10.5, 13.9)	16.0 (13.9, 18.1)
ASCVD	1.2 (0.0, 3.4)	2.6 (1.2, 4.1)	4.2 (3.1, 5.2)	6.6 (5.2, 7.9)
Total CVD	7.4 (3.1, 11.7)	11.4 (8.6, 14.3)	14.3 (12.5, 16.1)	18.9 (16.7, 21.2)
Risk at 75 years of age
Coronary heart disease	―	1.0 (0.0, 2.3)	1.5 (0.7, 2.3)	2.6 (1.5, 3.8)
Stroke	4.2 (0.0, 8.3)	7.3 (4.6, 10.0)	8.0 (6.2, 9.7)	8.9 (6.8, 11.1)
ASCVD	1.3 (0.0, 4.0)	1.6 (0.2, 3.0)	3.1 (2.0, 4.2)	3.4 (2.1, 4.6)
Total CVD	4.2 (0.0, 8.3)	8.4 (5.4, 11.4)	9.6 (7.7, 11.6)	10.2 (7.9, 12.5)

Lifetime risk by risk stratification was estimated to be the age of 85 years for individuals at 45, 55, 65, and 75 years, adjusted for competing risk. Abbreviations: LTR, lifetime risk; CI, confidence interval; ASCVD, atherosclerotic cardiovascular disease; and CVD, cardiovascular disease.

Table 3 shows the LTRs of CVD in women. The LTR of total CVD at 45 years old was 15.3% (95% CI, 13.1%-17.5%) in those with ≥ 2 major risk factors. The LTRs were higher in women with ≥ 2 major risk factors than those in other groups, while the LTR for women with ≥ 1 risk factor that was not optimal was the lowest among the risk groups.

Table 3.Lifetime risk of cardiovascular disease according to risk stratification in women

	All Risk Factors Optimal	≥ 1 Risk Factor Not Optimal	1 Major Risk Factor	≥ 2 Major Risk Factors
	LTR (95% CI), %	LTR (95% CI), %	LTR (95% CI), %	LTR (95% CI), %
Risk at 45 years of age
Coronary heart disease	0.5 (0.0, 1.2)	1.0 (0.5, 1.6)	1.3 (0.8, 1.7)	2.3 (1.5, 3.2)
Stroke	8.1 (4.8, 11.4)	7.6 (6.1, 9.0)	11.9 (10.5, 13.3)	13.3 (11.2, 15.3)
ASCVD	1.0 (0.0, 1.9)	2.0 (1.2, 2.8)	2.9 (2.1, 3.6)	3.9 (2.8, 5.1)
Total CVD	8.7 (5.3, 12.0)	8.5 (7.0, 10.0)	13.1 (11.6, 14.5)	15.3 (13.1, 17.5)
Risk at 55 years of age
Coronary heart disease	0.5 (0.0, 1.2)	0.9 (0.4, 1.3)	1.3 (0.8, 1.8)	2.1 (1.4, 2.9)
Stroke	7.8 (4.5, 11.1)	7.4 (5.9, 8.8)	11.0 (9.7, 12.3)	12.8 (10.8, 14.7)
ASCVD	1.0 (0.0, 1.9)	1.8 (1.0, 2.6)	2.8 (2.0, 3.5)	3.8 (2.7, 4.8)
Total CVD	8.4 (5.0, 11.7)	8.2 (6.6, 9.7)	12.1 (10.8, 13.5)	14.6 (12.6, 16.7)
Risk at 65 years of age
Coronary heart disease	0.5 (0.0, 1.1)	0.8 (0.4, 1.3)	1.2 (0.7, 1.7)	2.1 (1.3, 2.9)
Stroke	7.4 (4.0, 10.7)	6.5 (5.0, 7.9)	9.6 (8.3, 10.9)	11.7 (9.7, 13.6)
ASCVD	0.9 (0.0, 1.9)	1.8 (1.0, 2.6)	2.6 (1.9, 3.3)	3.8 (2.7, 4.8)
Total CVD	7.9 (4.4, 11.3)	7.2 (5.7, 8.7)	10.6 (9.3, 12.0)	13.5 (11.4, 15.6)
Risk at 75 years of age
Coronary heart disease	0.3 (0.0, 1.0)	0.5 (0.0, 0.9)	0.9 (0.4, 1.3)	1.1 (0.4, 1.8)
Stroke	6.2 (2.8, 9.7)	4.8 (3.4, 6.2)	6.5 (5.2, 7.7)	7.1 (5.2, 9.0)
ASCVD	0.8 (0.0, 1.8)	1.1 (0.4, 1.9)	2.0 (1.3, 2.8)	2.2 (1.2, 3.3)
Total CVD	6.6 (3.1, 10.1)	5.1 (3.6, 6.6)	7.2 (5.8, 8.5)	7.9 (5.9, 9.9)

Lifetime risk by risk stratifications was estimated to be the age of 85 years for individuals at 45, 55, 65, and 75 years, adjusted for competing risk. Abbreviations: LTR, lifetime risk; CI, confidence interval; ASCVD, atherosclerotic cardiovascular disease; and CVD, cardiovascular disease.

The LTR by index age from 45 years old was calculated and grouped by the presence of major risk factors (Table 4, Figs.2 and 3). Differences in LTR between the presence and absence of the risk factors were larger for those with hypertension (RR=1.76, P＜0.001), dyslipidemia (RR=1.35, P=0.001), and diabetes (RR=1.62, P＜0.001) than for those with a history of smoking. Similar findings were observed in women (Fig.3); however, there were no significant differences in the LTR between the groups in terms of dyslipidemia (P=0.130) and smoking status (P=0.311).

Table 4.Lifetime risk of total cardiovascular disease at 45 years of age by risk factors and lifetime risk rate ratios

Sex	Risk factor	Category	N	Person-years	Events	LTR (95% CI), %	LTR rate ratio	P value
Men	Hypertension	Yes	4,152	62,084	539	24.5 (22.4, 26.6)	1.76	＜0.001
		No	4,946	77,153	314	13.9 (12.2, 15.6)
	Dyslipidemia	Yes	1,922	29,227	214	23.4 (20.2, 26.5)	1.35	0.001
		No	7,176	110,010	639	17.4 (16.0, 18.8)
	Diabetes	Yes	594	8,489	108	29.1 (23.8, 34.3)	1.62	＜0.001
		No	8,504	130,748	745	17.9 (16.6, 19.3)
	Smoking	Yes	3,685	54,312	397	20.8 (18.7, 22.8)	1.20	0.009
		No	5,413	84,925	456	17.2 (15.6, 18.9)
Women	Hypertension	Yes	6,514	107,146	498	15.1 (13.6, 16.7)	1.57	＜0.001
		No	10,284	171,280	337	9.6 (8.4, 10.9)
	Dyslipidemia	Yes	5,145	84,055	297	12.8 (11.1, 14.5)	1.14	0.130
		No	11,653	194,371	538	11.3 (10.2, 12.3)
	Diabetes	Yes	529	8,225	64	21.9 (16.3, 27.5)	1.92	＜0.001
		No	16,269	270,201	771	11.4 (10.5, 12.3)
	Smoking	Yes	509	8,139	29	14.8 (8.9, 20.7)	1.26	0.311
		No	16,289	270,287	806	11.7 (10.8, 12.7)

Hypertension: blood pressure ≥ 140/90 mmHg or treated, dyslipidemia: non-HDL-cholesterol ≥ 170 mg/dL or treated, and diabetes: fasting glucose ≥ 126 mg/dL (nonfasting ≥ 200 mg/dL) or treated.

Abbreviations: LTR, lifetime risk, and CI, confidence interval.

Fig.2.

Lifetime risk of total cardiovascular disease in men with and without hypertension (A), dyslipidemia (B), diabetes (C), and smoking (D) at 45 years old

Fig.3.

Lifetime risk of total cardiovascular disease in women with and without hypertension (A), dyslipidemia (B), diabetes (C), and smoking (D) at 45 years old

Discussion

We determined the sex-specific LTRs of first-ever CHD, stroke, ASCVD, and total CVD, adjusted for the competing risk of death at 45 years old in Japanese individuals. The LTR of incident stroke was the highest among all CVDs, and the presence of hypertension and diabetes significantly affected the LTR of total CVD in men and women. At 45 years old, the LTR of total CVD in men with ≥ 2 major risk factors increased to 26.5%, indicating that behavioral changes to reduce risk factors are required from an early age. Furthermore, we assessed the LTR of ASCVD, as defined in the 2022 Japanese ASCVD guidelines⁴⁾. Compared to the group in which all risk factors were optimal, the LTR was found to increase substantially with the accumulation of risk factors.

The JPHC study documented the 10-year absolute risk of incident stroke²⁰⁾, coronary artery disease, infarction, and ischemic stroke²¹⁾. Even if men 45 years old had risk factors for both hypertension (160-179/100-109 mmHg) and diabetes, the predicted 10-year risk of stroke was estimated to be only 5%-6%. However, the LTR of stroke increased to 20.2%. The discrepancy between the 10-year risk and LTR was larger in younger age groups than in older groups. In Japan, the incidence of stroke was four times higher than that of CHD in the JPHC study⁶⁾. This influenced the difference in the LTR between CHD and stroke in this study. The primary goal of CVD prevention should focus on stroke events.

In the present study, risk stratification was based on a combination of hypertension, dyslipidemia, diabetes, and smoking as risk factors. Although previous studies did not consider prediabetes, the absence of prediabetes was assumed to be the optimal condition, since the presence of prediabetes increased the risk of CHD²²⁾. The LTR of ASCVD increased sharply with the number of risk factors compared with the LTR of stroke. This suggests that risk management is important for ASCVD prevention. In addition, this finding may be useful in that the importance of reducing even one risk factor can be used in risk communication rather than simply assessing LTRs according to the presence or absence of one risk factor.

The differences in LTRs by risk stratum were wider in men than in women. This implied that risk factors played a more important role in LTR in men than in women, especially because of the difference in smoking rates and the effects of dyslipidemia between men and women. In men with all optimal risk factors, the LTR for CVD remained low; however, in women, the two lowest risk factor groups had almost identical LTRs. Differences in LTR according to smoking status were not significant among women. The small number of smokers and lack of association may be due to the lack of statistical power. The Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH-JAPAN) study reported the LTR of CVD deaths stratified by a combination of risk factors⁹⁾. Although the criteria for risk stratification in EPOCH-JAPAN were different from ours, the effect of risk factor aggregation on LTR was more pronounced in men than in women.

Hypertension and diabetes had the greatest impact on the LTR of total CVDs²³⁾. The LTR differed 1.8-fold in men, 1.6-fold in women with and without hypertension, and 1.6-fold and 1.9-fold in women with and without diabetes in the present study. The impact of hypertension and diabetes on the LTR of CHD²⁴⁾, stroke^{25, 26)}, or both⁸⁾ was also found in prospective studies in Japan, although the LTR values varied by study and methodology. In addition, the JPHC prospective study reported the population-attributable fraction (PAF) of major risk factors for incident stroke and its subtypes²⁷⁾. The PAF of hypertension for total incident stroke was 25.8% (95% CI, 19.0%-31.9%), which was the highest among other major risk factors. Given the magnitude of the PAF of hypertension, controlling blood pressure to prevent CVD is important for ensuring the health of high-risk individuals and populations worldwide²⁸⁾.

LTRs of CVD are expected to be used in primary prevention to encourage lifestyle modifications and determine treatment initiation, especially for younger men and women who do not significantly increase the 10-year absolute risk. In Japan, annual health checkups, including screening for major risk factors, are officially conducted in the workplace and community, starting at 40 years old. We believe that LTR prediction will be beneficial for health management in public health settings. Nevertheless, there is insufficient evidence regarding whether or not communicating absolute risks to patients leads to behavioral changes such as quitting smoking or reducing unsaturated fatty acid intake²⁹⁾. A narrative review implies that personalized risk communication may encourage behavior changes³⁰⁾.

The strength of our study is that the JPHC study registered CHD and stroke based on the main hospital for a 20-year period in the general population. However, our study also had several limitations. First, the JPHC study recruited patients from nine communities as the study population, but those communities were in rural areas of Japan. Therefore, the results might not reflect the situation in urban areas of Japan. Second, we assessed LTRs up to 85 years old because the number of individuals ＞85 years old was too small to accurately calculate LTRs.

In conclusion, we identified a large impact of ≥ 2 major CVD risk factors on the LTR of total CVD at 45 years old in Japan. If risk factors remain the same, one in four men and one in six women will develop CVD during their lifetime. According to LTR evidence, prevention of CVD, which can be pursued by reducing CVD risk factors, should begin as early as midlife in both men and women.

Acknowledgements

Members of study groups: JPHC members are listed on the following site (as of 2021): https://epi.ncc.go.jp/en/jphc/781/8896.html.

The present study was supported by the National Cancer Center Research and Development Fund (since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour, and Welfare of Japan (from 1989 to 2010).

Conflicts of Interest

The authors state that they have no conflicts of interest (COIs).

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