Validation of N-Terminal Pro B-Type Natriuretic Peptide Threshold for Early Detection of Pre-Heart Failure in a General Japanese Population　― Toon Health Study ―

Abstract

Background: An N-terminal pro B-type natriuretic peptide (NT-proBNP) level above 125 pg/mL has been suggested as a universal marker for heart failure (HF). Furthermore, the Japanese Heart Failure Society (JHFS) advises follow-up when NT-proBNP exceeds 55 pg/mL, even if it remains below 125 pg/mL, for early HF detection. However, evidence supporting these thresholds remains limited.

Methods and Results: This prospective study, part of the Toon Health Study, included 573 participants with NT-proBNP levels below 125 pg/mL. Pre-HF progression was defined as reaching NT-proBNP levels of 125 pg/mL or higher after 5 years. The median age of the 573 participants was 61 years, and 70% were female. After 5 years, 53 (9.2%) participants developed pre-HF. Higher baseline NT-proBNP was associated with increased progression to pre-HF. A receiver operating characteristic curve identified 52.4 pg/mL NT-proBNP as the optimal threshold for predicting pre-HF progression, with an area under the curve of 0.78.

Conclusions: Even if NT-proBNP levels are below 125 pg/mL, especially when exceeding 52.4 pg/mL, close monitoring may be needed due to the risk of future pre-HF. These findings could support the JHFS’s recommendation.

N-terminal pro B-type natriuretic peptide (NT-proBNP) is valuable not only for guiding heart failure (HF) management in clinical practice but also as an effective biomarker for HF screening.¹ With aging of the population, the prevalence of HF has been steadily increasing. Early detection, followed by consistent monitoring and treatment, is essential for improving HF prognosis. As a result, the NT-proBNP threshold for HF screening has been reassessed based on accumulating evidence.

Both NT-proBNP and B-type natriuretic peptide (BNP) originate from proBNP and are useful for diagnosing HF, but NT-proBNP has certain advantages over BNP: it is non-bioactive, has a longer half-life than BNP, and remains stable at room temperature.^2,3 These features make NT-proBNP especially suitable for large-scale health checkups, as seen in the present study. Moreover, because NT-proBNP is unaffected by therapies that alter BNP degradation, such as an angiotensin receptor-neprilysin inhibitors (e.g., sacubitril/valsartan), the European Society of Cardiology (ESC) consensus statement recommends its use for HF evaluation.⁴

Due to its advantages, NT-proBNP has gained increasing recognition as a key marker for HF, leading to its inclusion in the 2021 Universal Definition of Heart Failure by the Japanese Heart Failure Society (JHFS), ESC, and American Heart Association (AHA).⁵ This definition set the HF diagnostic threshold at NT-proBNP ≥125 pg/mL. NT-proBNP levels have been observed to be relatively lower in HF with preserved ejection fraction (HFpEF), which has been rising in prevalence, than in HF with mildly reduced EF and HF with reduced EF (HFrEF).⁶ In response, the JHFS released a revised consensus report in 2023 to support earlier HF detection, recommending follow-up for individuals with NT-proBNP levels above 55 pg/mL, even if they do not meet the ≥125 pg/mL definition.⁷ In contrast, the ESC consensus statement advises follow-up at levels above 50 pg/mL.⁴ Thus, although the thresholds for early HF detection vary slightly between societies, they are largely similar. The aim of the present study was to determine NT-proBNP thresholds that can predict pre-HF development in the general Japanese population, using 5-year follow-up data from the Toon Health Study.

Methods

Toon Health Study

This study was conducted as part of the Toon Health Study, a prospective community-based cohort study focused on identifying cardiovascular disease risk factors in Toon City, Ehime Prefecture, Japan. The study’s details have been described in previous publications.^8–11 In summary, participants were recruited from around 22,000 Toon City residents aged 30–79 years. Baseline data collection occurred between 2009 and 2012 during the first phase, with additional recruitment phases from 2014 to 2017 and from 2018 to 2023. Eligibility criteria included: (1) voluntary participation by Toon City residents from June 2012 to October 2019; and (2) the absence of severe symptoms or illnesses. All participants provided written informed consent. Follow-up assessments were conducted every 5 years after enrollment.

Study Population and Measurements

Of the 2,119 Toon Health Study participants from June 2012 to October 2019, 32 with hemolysis of blood samples were excluded. Of the 2,087 participants in the Toon Health Study who had NT-proBNP levels measured at baseline, 638 completed the 5-year follow-up and were enrolled in the present study. After excluding 65 participants with baseline NT-proBNP levels of 125 pg/mL or higher, 573 participants were included in the analysis. A flowchart detailing participant selection is provided in Figure 1. NT-proBNP was measured using the Elecsys proBNP II immunoassay (Roche Diagnostics). Progression to pre-HF was defined as an NT-proBNP level of 125 pg/mL or more after 5 years according to the universal definition.⁵ Hypertension, dyslipidemia, and diabetes were defined as being under treatment or having a medical history of disease. The estimated glomerular filtration rate (eGFR) was calculated using a method based on age, sex, and serum creatinine concentration, as reported previously.¹²

Figure 1.

Flowchart showing recruitment of eligible participants. NT-proBNP, N-terminal pro B-type natriuretic peptide.

This study was undertaken in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Ehime University Graduate School of Medicine (Reference no. 2007004).

Statistical Analysis

Categorical variables are presented as counts and percentages, whereas continuous variables are presented as median values with an interquartile range (IQR). The Chi-squared test was used to compare categorical variables, and the Mann-Whitney U test was used for continuous variables. P<0.05 (two-tailed) was considered statistically significant. Receiver operating characteristic (ROC) analysis was performed to determine the NT-proBNP cut-off value for predicting pre-HF development. Univariate logistic regression was used to identify predictors of pre-HF progression, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Multivariate analyses were conducted, adjusting for age (continuous), sex (female: yes/no), and body mass index (BMI; continuous). eGFR (continuous) was included as a confounding variable because it is known to influence NT-proBNP levels in the general population.^11,13 Statistical analyses were conducted using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan).¹⁴

Results

The median age of participants was 61 years, with 70% being female. Of the 573 patients, 53 (9.2%) developed pre-HF after 5 years.

Table 1 presents baseline characteristics between residents with NT-proBNP ≥125 and <125 pg/mL after 5 years. Residents with NT-proBNP ≥125 pg/mL were older and had significantly lower renal function than those with NT-proBNP <125 pg/mL. Moreover, individuals with NT-proBNP ≥125 pg/mL at 5 years had higher baseline NT-proBNP levels. The frequency of progressing to pre-HF increased with higher baseline NT-proBNP levels (Figure 2). Only 4.2% of those with NT-proBNP ≤55 pg/mL developed pre-HF, compared with 17.9% of those with NT-proBNP >55 pg/mL. ROC curve analysis identified 52.4 pg/mL NT-proBNP as the optimal cut-off value for predicting pre-HF progression, with an area under the curve of 0.78 (Figure 3).

Table 1.

Baseline Characteristics in All Patients and According to NT-proBNP Levels at the 5-Year Follow-up

	All patients (n=573)	NT-proBNP at the 5-year follow-up		P value
		<125 pg/mL (n=520)	≥125 pg/mL (n=53)
Age (years)	61 [50–68]	61 [49–67]	68 [63–72]	<0.01
Female sex	70 (400)	69 (359)	77 (41)	0.27
BMI (kg/m2)	22.6 [20.5–24.7]	22.7 [20.6–24.8]	21.5 [20.1–24.0]	0.07
Waist (cm)	84 [77–90]	84 [77–90]	82 [77–87]	0.18
Systolic BP (mmHg)	121 [109–133]	120 [108–133]	125 [110–139]	0.09
Diastolic BP (mmHg)	75 [66–82]	76 [66–82]	73 [66–83]	0.96
Pulse rate (beats/min)	67 [61–73]	67 [62–73]	65 [60–74]	0.63
Coronary risk factors
Hypertension	21 (118)	21 (107)	21 (11)	1.00
Dyslipidemia	25 (141)	24 (123)	34 (18)	0.13
Diabetes	7 (39)	6 (33)	11 (6)	0.16
Current smoker	7 (42)	8 (41)	2 (1)	0.16
Laboratory data
Hemoglobin (g/dL)	13.5 [12.7–14.3]	13.5 [12.7–14.4]	13.4 [12.8–14.1]	0.87
Albumin (g/dL)	4.4 [4.3–4.4]	4.3 [4.1–4.4]	4.3 [4.1–4.5]	0.57
eGFR (mL/min/1.73 m2)	71.6 [63.1–80.3]	72.0 [63.5–80.9]	66.8 [59.0–76.2]	<0.01
Triglyceride (mg/dL)	89 [63–122]	89 [63–122]	85 [64–112]	0.99
LDL-C (mg/dL)	119 [99–137]	118 [99–137]	120 [105–137]	0.76
HDL-C (mg/dL)	62 [52–72]	62 [52–72]	65 [49–75]	0.61
HbA1c (%)	5.5 [5.3–5.8]	5.5 [5.3–5.8]	5.6 [5.4–5.9]	0.19
Uric acid (mg/dL)	4.9 [4.1–5.7]	4.9 [4.1–5.7]	4.9 [4.2–5.8]	0.53
hsCRP (mg/dL)	0.04 [0.02–0.07]	0.04 [0.02–0.07]	0.04 [0.02–0.06]	0.73
Baseline NT-proBNP (pg/mL)	45.6 [29.1–67.5]	42.5 [28.0–61.9]	75.9 [54.2–99.5]	<0.01

Unless indicated otherwise, data are given as the median [interquartile range] or % (n). BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; NT-proBNP, N-terminal pro B-type natriuretic peptide.

Figure 2.

Association between baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) levels and the frequency of progression to pre-heart failure (HF) after 5 years. Higher baseline NT-proBNP levels were linked to a greater incidence of pre-HF.

Figure 3.

Receiver operating characteristic curve analysis for predicting progression to pre-heart failure (HF) after 5 years. The optimal N-terminal pro B-type natriuretic peptide cut-off value for predicting pre-HF was 52.4 pg/mL, with an area under the curve (AUC) of 0.78.

The logistic regression analyses for predicting progression to pre-HF after 5 years are detailed in Table 2 (univariate analysis) and Table 3 (multivariate analysis). Multivariate analysis, adjusting for age, sex, BMI, and eGFR, identified baseline NT-proBNP as an independent predictor of progression to pre-HF (Table 3). The NT-proBNP cut-off value of 52.4 pg/mL found in the present study had a high OR of 4.30. Similarly, the NT-proBNP cut-off values recommended by the ESC (50 pg/mL) and JHFS (55 pg/mL) were also independent predictors of pre-HF development after 5 years.

Table 2.

Univariate Analysis of Baseline Characteristics Predicting Pre-HF Progression After 5 Years

	OR (95% CI)	P value
Age	1.09 (1.05–1.12)	<0.01
Female sex (vs. male)	1.53 (0.78–2.99)	0.21
BMI	0.91 (0.24–1.00)	0.05
Waist	0.98 (0.95–1.01)	0.14
Systolic BP	1.02 (1.00–1.03)	0.01
Diastolic BP	1.01 (0.98–1.03)	0.61
Pulse rate	1.00 (0.97–1.03)	0.81
Hypertension (vs. no hypertension)	1.01 (0.50–2.03)	0.98
Dyslipidemia (vs. no dyslipidemia)	1.66 (0.91–3.03)	0.10
Diabetes (vs. no diabetes)	1.88 (0.75–4.73)	0.18
Current smoker (vs. post or never smoker)	0.23 (0.03–1.67)	0.14
Hemoglobin	0.98 (0.79–1.22)	0.87
Albumin	1.23 (0.36–4.13)	0.74
eGFR	0.96 (0.94–0.99)	<0.01
Triglyceride	1,00 (0.99–1.00)	0.71
LDL-C	1.00 (0.99–1.01)	0.91
HDL-C	1.01 (0.99–1.02)	0.59
HbA1c	1.27 (0.81–1.99)	0.30
Uric acid	1.05 (0.84–1.32)	0.68
hsCRP	0.86 (0.26–2.84)	0.80
Baseline NT-proBNP	1.04 (1.03–1.05)	<0.01
Baseline NT-proBNP ≥52.4 pg/mL (yes vs. no; present study)	6.86 (3.45–13.6)	<0.01
Baseline NT-proBNP ≥50 pg/mL (yes vs. no; ESC recommendation)	5.91 (2.98–11.8)	<0.01
Baseline NT-proBNP ≥55 pg/mL (yes vs. no; JHFS recommendation)	5.04 (2.70–9.41)	<0.01

CI, confidence interval; ESC, European Society of Cardiology; HF, heart failure; JHFS, Japanese Heart Failure Society; OR, odds ratio. Other abbreviations as in Table 1.

Table 3.

Multivariate Analysis Predicting Pre-HF Progression After 5 Years

	Model 1		Model 2		Model 3		Model 4
	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
Age (per 1.0-year increase)	1.06 (1.02–1.10)	<0.01	1.07 (1.03–1.11)	<0.01	1.07 (1.03–1.11)	<0.01	1.07 (1.03–1.11)	<0.01
Female sex	1.35 (0.63–2.90)	0.44	1.45 (0.69–3.06)	0.33	1.48 (0.70–3.12)	0.30	1.50 (0.71–3.14)	0.29
BMI (per 1.0-kg/m2 increase)	0.92 (0.83–1.01)	0.09	0.91 (0.82–1.01)	0.06	0.90 (0.82–1.00)	0.06	0.90 (0.82–1.00)	0.05
eGFR (per 1.0-mL/min/1.73 m2 increase)	0.99 (0.96–1.01)	0.32	0.99 (0.96–1.01)	0.31	0.99 (0.96–1.01)	0.24	0.99 (0.96–1.01)	0.25
Baseline NT-proBNP (per 1.0-pg/mL increase)	1.03 (1.02–1.04)	<0.01
Baseline NT-proBNP ≥52.4pg/mL (present study)			4.30 (2.08–8.89)	<0.01
Baseline NT-proBNP ≥50pg/mL (ESC recommendation)					3.59 (1.73–7.45)	<0.01
Baseline NT-proBNP ≥55pg/mL (JHFS recommendation)							3.10 (1.59–6.07)	<0.01

^AAll models were adjusted for age (continuous variable), sex (female: yes/no), and body mass index (BMI; continuous variable). eGFR, estimated glomerular filtration rate; ESC, European Society of Cardiology; JHFS, Japanese Heart Failure Society; NT-proBNP, N-terminal pro B-type natriuretic peptide.

Discussion

Based on data from the general Japanese population in the Toon Health Study, the present study found that: (1) despite NT-proBNP levels being below125 pg/mL, 9.2% of participants developed pre-HF after 5 years; (2) higher baseline NT-proBNP levels were associated with increased progression to pre-HF; (3) baseline NT-proBNP was an independent predictor of pre-HF development; and (4) the baseline NT-proBNP threshold for predicting pre-HF was 52.4 pg/mL, showing a high OR. These thresholds are similar to those recommended by the JHFS and ESC.

Universal NT-proBNP Threshold for HF Detection

HF is a clinical syndrome with diverse causes and mechanisms, and its definition has varied across major guidelines. In 2021, the JHFS, ESC, and AHA established a collaborative international definition of HF.⁵ This definition set the NT-proBNP threshold for diagnosing HF at ≥125 pg/mL. HF is defined as a “clinical syndrome with current or prior symptoms and/or signs caused by a structural and/or functional cardiac abnormality.”⁵ Even if clinical criteria are not met, individuals with NT-proBNP ≥125 pg/mL are classified as pre-HF or Stage B HF in the collaborative statement. In addition, the JHFS released a revised consensus report in 2023, which considered NT-proBNP levels of 125 pg/mL or higher as indicative of progression from pre-HF to HF, recommending further assessment or referral to a cardiologist.⁷ Therefore, the universal NT-proBNP threshold of ≥125 pg/mL is crucial for managing HF, regardless of symptoms or structural/functional cardiac abnormalities.

Stricter NT-proBNP Threshold for Earlier HF Detection

NT-proBNP levels can be affected by factors such as age, sex, BMI, and renal function.¹¹ Choi et al. previously reported that higher age, female sex, and reductions in obesity-related parameters were associated with higher NT-proBNP levels among 39,937 healthy adults.¹³ However, the present study found that NT-proBNP remained an independent predictor of future pre-HF even after adjusting for age, sex, BMI, and eGFR. The study identified an NT-proBNP threshold of 52.4 pg/mL for predicting pre-HF development. This threshold is close to the JHFS consensus value of 55 pg/mL NT-proBNP for early HF detection and the ESC’s 50-pg/mL NT-proBNP cut-off for the “heart stress” condition.⁴ “Heart stress” refers to a condition where elevated plasma NT-proBNP levels indicate myocardial stress due to risk factors, even in the absence of structural heart disease or functional abnormalities, suggesting preclinical HF. The JHFS-recommended NT-proBNP threshold of 55 pg/mL is based on the upper normal limit of 54.5 pg/mL found in healthy volunteers.¹⁵ However, this threshold has limitations: (1) it is based on data from 2003; and (2) it was derived from a relatively small sample of 67 healthy individuals. In contrast, the ESC recommended an NT-proBNP cut-off of 50 pg/mL, supported by a 2016 study by the Natriuretic Peptides Studies Collaboration, which identified an increased risk of HF with NT-proBNP levels above 50 pg/mL.^16,17 Nonetheless, the link between NT-proBNP levels exceeding this threshold and progression to HF has not been fully established. Japanese populations are reported to have a lower BMI and lower obesity rates than European/US populations.¹⁸ Given higher BMI results in lower BNP/NT-proBNP, it should be noted that obesity may lead to delayed detection of HF and an underestimation of its severity.^13,19,20 Our results are consistent with these previous reports (Supplementary Figure 1A,1B). Therefore, the cut-off of 50 pg/mL for NT-proBNP recommended by the ESC guideline may require reconsideration when used in Japanese populations. Although the cut-off of 50 pg/mL NT-proBNP was an independent predictor of pre-HF at 5 years in our study population, further discussion is needed for international unification of the NT-proBNP threshold for early detection of pre-HF.

Our study provides additional evidence supporting that individuals with NT-proBNP levels above 52.4 pg/mL are at a higher risk of progressing to pre-HF, aligning with recommendations from both the JHFS and ESC. Stricter thresholds for earlier HF detection are closely linked to increased cases of HFpEF. HFpEF, which has a mortality rate similar to HFrEF, often presents with lower BNP levels than in HFrEF, making a stricter threshold necessary for early diagnosis.^21–23 NT-proBNP has been reported to be useful in predicting the development of chronic kidney disease (CKD) as well as HF.²⁴ The ability of baseline NT-proBNP to predict the development CKD in the present study is described in the Supplementary Files. NT-proBNP is a biomarker reflecting renal as well as cardiac function.^25,26 Moreover, because NT-proBNP is metabolized primarily in the kidneys, NT-proBNP is known to increase with worsening renal function. Therefore, it is very important to verify whether the increase in NT-proBNP ≥125 pg/mL after 5 years in the present study is solely due to worsening renal function. To address this concern, further analysis was conducted on the association between the increase in NT-proBNP ≥125 pg/mL after 5 years and CKD progression. The results presented in the Supplementary Files suggest that the increase in NT-proBNP ≥125 pg/mL after 5 years may be due to many factors, and not just due to CKD progression alone.

Clinical Importance of Detecting HFpEF in the General Population

This study, which focused on a general Japanese population and excluded residents with NT-proBNP ≥125 pg/mL, found that 9.2% of participants progressed to pre-HF after 5 years. Supporting our findings, Young et al. previously reported that 20% of individuals with preclinical (Stages A and B) HF progressed to a later HF stage over a 4-year period.²⁷ However, their study showed that NT-proBNP was associated with progression in Stage B but not Stage A HF. Their results differ from ours, partly due to their older data collection period (1997–2000).²⁷ Because our study also included individuals not classified as Stage A/B, our findings may be more relevant for screening the general population for the development of HF.

HFpEF has been linked to subclinical HF progression in the general population.¹¹ Thus, examining the relationship between HFpEF and NT-proBNP is crucial for validating thresholds for early HF detection. Factors that increase NT-proBNP often overlap with those associated with HFpEF. For example, advanced age, female sex, anemia, hypoalbuminemia, renal insufficiency, dyslipidemia, and diabetes are significant factors associated with HF, especially HFpEF, and influence NT-proBNP levels.^23,28–34 Inoue et al. developed a prediction model for NT-proBNP using data from the Toon Health Study, incorporating 10 indicators from health checkups: demographic variables (age, sex, and BMI), physiological measurements (diastolic blood pressure and heart rate), and blood test results (hemoglobin, albumin, total cholesterol, HbA1c, and eGFR).¹¹ This model is notably accurate for predicting NT-proBNP levels ≤400 pg/mL, which reflects heart stress, pre-HF, or early-stage HF. Therefore, residents with elevated NT-proBNP levels may be at greater risk of developing pre-HF or HFpEF.

Effective Utilization of the Results of This Study

In general, circulating NT-proBNP levels are reported to be higher in women than in men and increase with age.¹³ In fact, circulating NT-proBNP levels by age and sex in our study are consistent with previous reports (Supplementary Figure 3A).¹³ Because our data are for a cohort from a local city in Ehime, Japan, the age distribution is skewed towards the elderly compared with Japan as a whole (Supplementary Figure 3B). Although the results of the present study were adjusted by age and sex, caution should be paid in applying the NT-proBNP threshold for the early detection of pre-HF to Japan. However, Japan is aging, and rural areas anticipate the age distribution of future Japan. Therefore, our results could provide valuable information for Japan’s aging population. The difference in age distribution is more pronounced in urban areas. To validate the NT-proBNP threshold for the younger population, it is necessary to re-examine data from urban areas.

Study Limitations

This study has some limitations. First, the study population was restricted to Toon City, which may introduce selection bias compared with the broader general population. Toon City, a rural area in the Shikoku region, has a different age distribution compared with larger cities and a predominantly female population. Although NT-proBNP was an independent predictor of HF development in multivariate analysis, even after adjusting for sex, further validation is needed in other regions. Second, the study relied on a limited dataset from health checkups, which includes some clinical information, such as medical history and lifestyle factors, but does not capture all relevant details. This limitation affects the interpretation of the results. The JHFS defines pre-HF as NT-proBNP >125 pg/mL concomitant with cardiac morphological changes or dysfunction.⁷ However, in the present study, pre-HF was defined solely by elevated NT-proBNP with reference to the universal definition.⁵ Given structural and functional cardiac abnormalities were not assessed due to the lack of echocardiography, the study may overestimate pre-HF as defined by the JHFS. We also lack data on the presence or absence of atrial fibrillation, which influences NT-proBNP levels. Although individuals with high baseline NT-proBNP levels were excluded, their potential effect on the results cannot be entirely dismissed. Finally, we do not have detailed data on the occurrence of cardiovascular events during the study period. Thus, this study could not exclude participants who developed cardiovascular disease. A 4-year observational study of 3,610 Japanese outpatients who had a history of and/or risk factors for cardiovascular disease reported a very low incidence of cardiovascular events (3.6%).³⁵ Because our study was conducted in a general Japanese population, the incidence of cardiovascular events is expected to be even lower. Therefore, this limitation may have little impact on the results of the present study. To clarify the association between NT-proBNP levels and the occurrence of cardiovascular events, future studies with a larger number of cases and longer observation periods are needed.

Conclusions

NT-proBNP can predict the future development of pre-HF in the general Japanese population. This study found that a threshold of 52.4 pg/mL NT-proBNP for the early detection of pre-HF aligns with the JHFS recommendation of 55 pg/mL and the ESC recommendation of 50 pg/mL. NT-proBNP is a straightforward and effective test, and these findings may aid in the early detection of pre-HF in the general population.

Sources of Funding

This study was funded by Roche Diagnostics, which also provided the test kits for NT-proBNP quantification (Elecsys proBNP II) used in the immunoassays.

Disclosures

The authors have no conflicts of interest to declare.

IRB Information

This study was approved by Ehime University Graduate School of Medicine (Reference no. 2007004).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0774

References

• 1.   McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021; 42: 3599–3726, doi:10.1093/eurheartj/ehab368.
• 2.   Pemberton CJ, Johnson ML, Yandle TG, Espiner EA. Deconvolution analysis of cardiac natriuretic peptides during acute volume overload. Hypertension 2000; 36: 355–359, doi:10.1161/01.hyp.36.3.355.
• 3.   Yeo KT, Wu AH, Apple FS, Kroll MH, Christenson RH, Lewandrowski KB, et al. Multicenter evaluation of the Roche NT-proBNP assay and comparison to the Biosite Triage BNP assay. Clin Chim Acta 2003; 338: 107–115, doi:10.1016/j.cccn.2003.08.016.
• 4.   Bayes-Genis A, Docherty KF, Petrie MC, Januzzi JL, Mueller C, Anderson L, et al. Practical algorithms for early diagnosis of heart failure and heart stress using NT-proBNP: A clinical consensus statement from the Heart Failure Association of the ESC. Eur J Heart Fail 2023; 25: 1891–1898, doi:10.1002/ejhf.3036.
• 5.   Bozkurt B, Coats AJ, Tsutsui H, Abdelhamid CM, Adamopoulos S, Albert N, et al. Universal definition and classification of heart failure: A report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail 2021; 23: 352–380, doi:10.1002/ ejhf.2115.
• 6.   Verbrugge FH, Omote K, Reddy YN, Sorimachi H, Obokata M, Borlaug BA. Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality. Eur Heart J 2022; 43: 1941–1951, doi:10.1093/eurheartj/ehab911.
• 7.   The Japanese Heart Failure Society. Japan: Statement on the treatment of heart failure using blood BNP and NT-proBNP, revised 2023 [in Japanese]. https://www.asas.or.jp/jhfs/topics/bnp20231017.html (accessed February 27, 2025).
• 8.   Kawamura R, Tabara Y, Takata Y, Maruyama K, Takakado M, Hadate T, et al. Association of a SNP in the IAPP gene and hyperglycemia on β-cell dysfunction in type 2 diabetes: The Toon genome study. Diabetol Int 2022; 13: 201–208, doi:10.1007/s13340-021-00523-4.
• 9.   Uesugi Y, Maruyama K, Saito I, Tomooka K, Takata Y, Kawamura R, et al. A cross-sectional study of the relationship of Timed Up & Go test with physical characteristics and physical activity in healthy Japanese: The Toon health study. Healthcare (Basel) 2021; 9: 933, doi:10.3390/healthcare9080933.
• 10.   Yokoyama M, Saito I, Ueno M, Kato H, Yoshida A, Kawamura R, et al. Low birthweight is associated with type 2 diabetes mellitus in Japanese adults: The Toon health study. J Diabetes Investig 2020; 11: 1643–1650, doi:10.1111/jdi.13274.
• 11.   Inoue K, Yamamoto K, Higashi H, Takata Y, Inaba S, Miyazaki S, et al. A prediction model for estimating NT-proBNP in a general Japanese population: The Toon health study. ESC Heart Fail 2024; 11: 1483–1492, doi:10.1002/ehf2.14691.
• 12.   Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982–992, doi:10.1053/j.ajkd.2008.12.034.
• 13.   Choi HI, Lee MY, Oh BK, Lee SJ, Kang JG, Lee SH, et al. Effects of age, sex, and obesity on N-terminal pro B-type natriuretic peptide concentrations in the general population. Circ J 2021; 85: 647–654, doi:10.1253/circj.CJ-20-1104.
• 14.   Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 2013; 48: 452–458, doi:10.1038/bmt.2012.244.
• 15.   Seino Y, Ogawa A, Yamashita T, Fukushima M, Ogata K, Fukumoto H, et al. Application of NT-proBNP and BNP measurements in cardiac care: A more discerning marker for the detection and evaluation of heart failure. Eur J Heart Fail 2004; 6: 295–300, doi:10.1016/j.ejheart.2003.12.009.
• 16.   Natriuretic Peptides Studies Collaboration, Willeit P, Kaptoge S, Welsh P, Butterworth AS, Chowdhury R, Spackman SA, et al. Natriuretic peptides and integrated risk assessment for cardiovascular disease: An individual-participant-data meta-analysis. Lancet Diabetes Endocrinol 2016; 4: 840–849, doi:10.1016/S2213-8587(16)30196-6.
• 17.   Verma S, Sharma A, Kanumilli N, Butler J. Predictors of heart failure development in type 2 diabetes: A practical approach. Curr Opin Cardiol 2019; 34: 578–583, doi:10.1097/HCO.0000000000000647.
• 18.   Yatsuya H, Yamagishi K, Iso H. Adiposity and risk of cardiovascular diseases in Japan: Secular trend, individual level associations and causal pathway - implications for the prevention of cardiovascular diseases in societies with rapid economic development. EPMA J 2011; 2: 65–73, doi:10.1007/s13167-011-0071-4.
• 19.   Ishihara S, Hiramitsu S, Kanaoka K, Taki M, Nakagawa H, Ueda T, et al. New conversion formula between B-type natriuretic peptide and N-terminal-pro-B-type natriuretic peptide: Analysis from a multicenter study. Circ J 2022; 86: 2010–2018, doi:10.1253/circj.CJ-22-0032.
• 20.   Komukai K, Minai K, Arase S, Ogawa T, Nakane T, Nagoshi T, et al. Impact of body mass index on clinical outcome in patients hospitalized with congestive heart failure. Circ J 2012; 76: 145–151, doi:10.1253/circj.cj-11-0727.
• 21.   Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide to detect preclinical ventricular systolic or diastolic dysfunction: A community-based study. Circulation 2004; 109: 3176–3181, doi:10.1161/01.CIR.0000130845.38133.8F.
• 22.   Luchner A, Burnett JC Jr, Jougasaki M, Hense HW, Heid IM, Muders F, et al. Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens 2000; 18: 1121–1128, doi:10.1097/00004872-200018080-00018.
• 23.   Pieske B, Tschöpe C, de Boer RA, Fraser AG, Anker SD, Donal E, et al. How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J 2019; 40: 3297–3317, doi:10.1093/eurheartj/ehz641.
• 24.   Nakayama S, Satoh M, Metoki H, Murakami T, Asayama K, Hara A, et al. N-Terminal pro-B-type natriuretic peptide is a predictor of chronic kidney disease in an Asian general population: The Ohasama study. Circ Rep 2019; 2: 24–32, doi:10.1253/circrep.CR-19-0044.
• 25.   Tsutsui H, Momomura SI, Saito Y, Ito H, Yamamoto K, Sakata Y, et al. Long-term treatment with sacubitril/valsartan in Japanese patients with chronic heart failure and reduced ejection fraction: Open-label extension of the PARALLEL-HF study. Circ J 2023; 88: 43–52, doi:10.1253/circj.CJ-23-0174.
• 26.   Luo M, Zhu Z, Zhang L, Zhang S, You Z, Chen H, et al. Predictive value of N-terminal pro B-type natriuretic peptide for contrast-induced nephropathy non-recovery and poor outcomes among patients undergoing percutaneous coronary intervention. Circ J 2023; 87: 258–265, doi:10.1253/circj.CJ-22-0399.
• 27.   Young KA, Scott CG, Rodeheffer RJ, Chen HH. Progression of preclinical heart failure: A description of Stage A and B heart failure in a community population. Circ Cardiovasc Qual Outcomes 2021; 14: e007216, doi:10.1161/CIRCOUTCOMES.120.007216.
• 28.   Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: Impact of age and gender. J Am Coll Cardiol 2002; 40: 976–982, doi:10.1016/s0735-1097(02)02059-4.
• 29.   Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, et al. Impact of obesity on plasma natriuretic peptide levels. Circulation 2004; 109: 594–600, doi:10.1161/01.CIR.0000112582.16683.EA.
• 30.   Hussain A, Sun W, Deswal A, de Lemos JA, McEvoy JW, Hoogeveen RC, et al. Association of NT-ProBNP, blood pressure, and cardiovascular events: The ARIC study. J Am Coll Cardiol 2021; 77: 559–571, doi:10.1016/j.jacc.2020.11.063.
• 31.   van Kimmenade RR, Januzzi JL Jr, Bakker JA, Houben AJ, Rennenberg R, Kroon AA, et al. Renal clearance of B-type natriuretic peptide and amino terminal pro-B-type natriuretic peptide a mechanistic study in hypertensive subjects. J Am Coll Cardiol 2009; 53: 884–890, doi:10.1016/j.jacc.2008.11.032.
• 32.   Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: Insights from a cohort of 12 065 patients with new-onset heart failure. Circulation 2003; 107: 223–225, doi:10.1161/01.cir.0000052622.51963.fc.
• 33.   Takeuchi H, Sata M. The relationship among brain natriuretic peptide (BNP), cholesterol and lipoprotein. Heart Asia 2012; 4: 11–15, doi:101136/heartasia-2011-010042.
• 34.   Ceriello A, Catrinoiu D, Chandramouli C, Cosentino F, Dombrowsky AC, Itzhak B, et al. Heart failure in type 2 diabetes: Current perspectives on screening, diagnosis and management. Cardiovasc Diabetol 2021; 20: 218, doi:10.1186/s12933-021-01408-1.
• 35.   Taki M, Ishiyama Y, Mizuno H, Komori T, Kono K, Hoshide S, et al. Sex differences in the prognostic power of brain natriuretic peptide and N-terminal pro-brain natriuretic peptide for cardiovascular events: The Japan Morning Surge-Home Blood Pressure Study. Circ J 2018; 82: 2096–2102, doi:10.1253/circj.CJ-18-0375.