B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction　― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

Abstract

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is increasing with aging of the population. Plasma levels of B-type natriuretic peptide (BNP) increase in proportion to the severity of left ventricular (LV) dysfunction. The object of this study was to examine the plasma levels of BNP in HFpEF to better understand the pathogenesis of HFpEF as compared with HF with reduced EF (HFrEF).

Methods and Results: The study subjects comprised 468 HFpEF patients (158 men, 310 women, mean age 81.3±9.6 years) and 126 HFrEF patients (77 men, 49 women, mean age 75.4±12.0 years) who underwent echocardiography and routine clinical examinations including plasma BNP. Age, female prevalence, systolic blood pressure and pulse pressure were higher in the HFpEF patients than in the HFrEF patients (P<0.0001, P<0.001, P<0.0001, and P<0.0001, respectively). Plasma BNP levels, LV diastolic dimensions, and LV mass index (LVMI) were lower (P<0.0001, P<0.0001, and P<0.0001, respectively), while relative wall thickness was higher (P<0.0001) in the HFpEF patients than in the HFrEF patients. Multiple regression analysis revealed that LVMI, EF, plasma levels of albumin, C-reactive protein, and uric acid were the predictors of BNP levels (P<0.001, P<0.001, P=0.009, P=0.012, and P=0.018, respectively).

Conclusions: Plasma BNP levels were lower and related to aging-related LV concentric remodeling/hypertrophy in HFpEF patients as compared with HFrEF patients, who were associated predominantly with eccentric LV hypertrophy.

The heart is an endocrine organ producing natriuretic peptides such as A-type (ANP) and B-type natriuretic peptide (BNP), the former mainly from the atrium and the latter from the left ventricle (LV).^1–4 Both ANP and BNP production increases in proportion to the severity of LV dysfunction.^1–4 Heart failure (HF) is a clinical syndrome resulting from LV dysfunction and the ejection fraction (EF) has traditionally been used as an indicator of LV dysfunction.^4–7 The plasma level of BNP has therefore been widely used as a marker of diagnosis, severity, and prognosis of HF.^4–7 It is now recognized that more than half of the patients with HF have preserved EF, or HF with preserved EF (HFpEF), and its prevalence is increasing as the population ages.^6–8 However, the underlying mechanisms of HFpEF, as well as the involvement of BNP in HFpEF, are not well understood.^6–9 HFpEF is a disease predominantly associated with aging. The object of the present study was to examine the relevance of BNP to HFpEF and thereby to better understand the underlying pathogenesis of HFpEF focusing on the relationship with aging as compared with HFrEF.

Methods

Study Subjects

The study subjects consisted of 594 consecutive Japanese patients with HF (235 men and 359 women, mean age 80.0±10.4 years) who were admitted or referred to Kumamoto Kinoh Hospital between May 2012 and April 2015. They included 468 patients with HFpEF (158 men and 310 women, mean age 81.3±9.6 years) (HFpEF group) and 126 patients with HFrEF (77 men and 49 women, mean age 75.4±12.0 years) (HFrEF group) who presented with dyspnea, fatigue and/or fluid retention and had signs of LV dysfunction on echocardiography and elevated plasma BNP levels >100 pg/mL. HFpEF was defined as HF with LVEF ≥50% and early diastolic mitral flow velocity (E)/tissue annular motion velocity (e’) or E/e’ ≥15, and HFrEF as HF with LVEF <50%.⁶ Patients with valvular disease, pericardial disease, congenital heart disease, acute inflammatory disease, acute myocardial infarction, high-output HF, or infiltrative cardiomyopathies were excluded from the study. Patients in whom adequate cardiac images could not be obtained were also excluded. This study was conducted in accordance with the Declaration of Helsinki and approved by the institutional ethics committees and informed consent was obtained from each patient.

Echocardiography

Echocardiography, including 2D, pulsed and continuous wave Doppler, color flow Doppler, and tissue Doppler imaging, was performed using the iE33 Ultrasound System (Philips Ultrasound Co., Bothell, WA, USA), with the majority of both the HFpEF and the HFrEF patients similarly stable (NYHA functional class II) on therapy at the time of examination either as an ambulatory outpatient (461 patients) or inpatient (74 patients) on the same day or within 2 days of blood sampling for BNP. LV and atrial linear dimensions were measured from 2D echocardiographic images and LVEF, E/e’, LV diastolic dimension (LVDd), LV systolic dimension (LVDs), LV mass index (LVMI), left atrial dimension (LAD), interventricular septal thickness (IVST), posterior wall thickness (PWT), relative wall thickness (RWT), stroke volume, and EF were measured and calculated according to the recommendations of American Society of Echocardiography and European Association of Echocardiography.¹⁰ EF was calculated using the modified biplane Simpson method. E/e’(septal) was used as a surrogate marker of LV end-diastolic pressure. LV mass was estimated using linear measurements from 2D images and indexed to body surface area as the LVMI. LV hypertrophy (LVH) was defined as LVMI >115 g/m² in men or >95 g/m² in women. LV geometry was classified according to RWT, defined as (2×diastolic PWT)/LVDd, and LVMI: normal-RWT ≤0.42 and no LVH; eccentric hypertrophy-RWT ≤0.42 and LVH; concentric remodeling-RWT >0.42 and no LVH; concentric hypertrophy-RWT >0.42 and LVH.¹⁰ Echocardiography was performed by experienced sonographers blinded to the clinical information. The interobserver correlation coefficient of the PWT measurement was 0.869 (95% confidence interval 0.757–0.980) measured in 50 HF patients.

Blood Chemistry Measurements

Plasma BNP levels were measured using a specific immunoradiometric assay for human BNP (TOSOH Corp., Tokyo, Japan) on the same day or within 2 days of echocardiography. Blood samples for measurement of clinical chemistry and other data were collected from the patient in a supine position after an overnight fast. The biochemical and other analyses were done using standard laboratory procedures.

Statistical Analysis

The data are expressed as the mean±SD or median (25th, 75th percentiles) for continuous variables and differences within the group were evaluated with unpaired t-test or the Mann-Whitney rank sum test. For discrete variables, data were expressed as counts and percentages and analyzed with the Chi-square test. The correlation between variables was assessed using Spearman’s rank correlation coefficient. A multiple linear regression analysis was performed to determine the predictors of BNP after conversion into a natural logarithm. Predictor variables were included on the basis of theoretical grounds, the results of a bivariate analysis and collinearity. A two-tailed value of P<0.05 was considered to be as statistically significant. The analyses were done using the STATA software program (STATA 11.0, STATA Corp., College Station, TX, USA).

Results

Comparison of Clinical Characteristics of the HFpEF and HFrEF Groups

Table 1 compares the clinical characteristics of the HFpEF and HFrEF groups. The number of HFpEF patients was 3.7-fold (468 vs. 126) higher than that of HFrEF patients. Age, female sex, systolic blood pressure, and pulse blood pressure were higher (P<0.0001 P<0.001, P<0.0001, and P<0.0001, respectively), and plasma BNP, hemoglobin, red blood cells, creatinine, and uric acid were lower (P<0.0001, P<0.0001, P=0.0003, P=0.0011, and P=0.0114, respectively) in the HFpEF than in the HFrEF groups. Thus, HFpEF was more prevalent in the aged, particularly women (Figure 1), and was associated with higher systolic blood pressure, pulse pressure or aortic stiffness, and lower plasma BNP levels than HFrEF. As for comorbidities, hypertension was more prevalent (P=0.026), and old myocardial infarction, dyslipidemia, and diabetes mellitus less prevalent, in the HFpEF than in HFrEF (P<0.001, P=0.003, and P=0.007, respectively). The echocardiographic findings revealed that LVDd, and LVMI were lower (P<0.0001 and P<0.0001, respectively), whereas RWT and stroke volume index were higher (P<0.0001 and P<0.0001, respectively) in the HFpEF than in the HFrEF group (Table 2). Thus, the hearts of the HFpEF patients displayed a smaller LV cavity size and relatively thicker wall and higher prevalence of LV concentric remodeling/hypertrophy (87% vs. 49%, P<0.001) and much less prevalence of eccentric hypertrophy (9% vs. 46%, P<0.001) associated with stiffer aortas than those with HFrEF with similarly increased E/e’ or LV end-diastolic pressures (Tables 1,2; Figure 2).

Table 1. Comparison of Clinical Characteristics of HFpEF and HFrEF Patients

Variable	HFpEF (n=468)	HFrEF (n=126)	P value
Age (years)	81.3±9.6	75.4±12.0	<0.0001
Sex (men, %)	158 (34)	77 (61)	<0.001
BMI (kg/m2)	21.2 (18.4, 24.2)	22.0 (18.7, 24.7)	0.34
Systolic BP (mmHg)	131±23	121±21	<0.0001
Diastolic BP (mmHg)	71±14	70±14	0.69
Pulse BP (mmHg)	60±18	50±17	<0.0001
Heart rate (beats/min)	73±15	77±20	0.08
BNP (pg/mL)	197 (132, 317)	365 (206, 696)	<0.0001
Hemoglobin (g/dL)	11.4±2.0	12.4±2.1	<0.0001
Red blood cells (×104/mL)	365 (334, 408)	387 (334, 444)	0.0003
Creatinine (mg/dL)	0.9 (0.7, 1.1)	1.0 (0.8, 1.3)	0.0011
Uric acid (mg/dL)	5.5 (4.6, 6.6)	5.9 (5.1, 7.4)	0.0114
Albumin (g/dL)	3.7 (3.3, 3.9)	3.6 (3.2, 3.8)	0.12
Blood sugar (mg/dL)	115 (99, 139)	112 (98, 136)	0.48
eGFR (mL/min/1.73 m2)	53 (40, 66)	50 (37, 62)	0.47
White blood cells (×102/mL)	59 (47, 76)	61 (47, 77)	0.40
Platelets (×104/mL)	17.9 (13.8, 22.1)	18.0 (13.4, 22.5)	0.96
CRP (mg/L)	2.4 (0.7, 14.0)	3.5 (1.0, 14.0)	0.37
Hypertension (%)	79.9	70.6	0.026
Old myocardial infarction (%)	17.1	41.3	<0.001
Dyslipidemia (%)	37.2	51.6	0.003
Diabetes mellitus (%)	44.4	57.9	0.007
Atrial fibrillation (%)	33.8	38.1	0.35
CKD (eGFR <30) (%)	14.2	16.4	0.57
Obesity (BMI ≥25) (%)	21.2	24.5	0.46
ACEI/ARB (%)	58.3	71.4	0.007
β-blocker (%)	34.8	55.6	<0.001
MR antagonist (%)	16.9	41.2	<0.001
Diuretic (%)	38.9	54.0	0.002
Calcium-channel blocker (%)	46.4	33.3	0.009

ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin-II receptor blocker; BMI, body mass index; BNP, B-type natriuretic peptide; BP, blood pressure; CKD, chronic kidney disease; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MR, mineralocorticoid receptor.

Figure 1.

Prevalence of HFpEF increased with age and was higher in women than in men. HFpEF, heart failure with preserved ejection fraction.

Table 2. Comparison of Echocardiographic Parameters for HFpEF and HFrEF

Variable	HFpEF (n=468)	HFrEF (n=126)	P value
LVDd (mm)	42 (38, 47)	50 (44, 56)	<0.0001
LVMI (g/m2)	120 (102, 143)	142 (118, 171)	<0.0001
RWT	0.52 (0.47, 0.60)	0.43 (0.37, 0.52)	<0.0001
EF (%)	66 (61, 73)	41 (33, 45)	<0.0001
SVI (mL/m2)	37 (30, 44)	28 (23, 35)	<0.0001
LAD (mm)	38 (32, 44)	41 (35, 46)	0.0203
e’	4.4 (3.4, 5.4)	4.1 (3.2, 5.0)	0.0481
E/e’	18.3 (16.4, 21.3)	19.1 (14.1, 23.1)	0.30
IVST (mm)	12.0 (10.6, 13.1)	11.8 (10.3, 13.0)	0.20
PWT (mm)	11.0 (10.2, 12.3)	11.0 (9.8, 11.9)	0.14

E/e’, ratio of early transmittal velocity to tissue Doppler mitral annular early diastolic velocity; e’, tissue Doppler mitral annular early diastolic velocity; EF, ejection fraction; IVST, interventricular septal thickness; LAD, left atrial dimension; LVDd, left ventricular diastolic dimension; LVMI, left ventricular mass index; PWT, posterior wall thickness; RWT, relative wall thickness; SVI, stroke volume index. Other abbreviations as in Table 1.

Figure 2.

Comparison of left ventricular geometry in HFpEF and HFrEF. The prevalence of concentric remodeling/hypertrophy was higher, whereas that of eccentric hypertrophy was lower in HFpEF than in HFrEF patients. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Correlation of Plasma BNP With Echocardiographic and Variable Clinical Data

Table 3 shows the associations of plasma BNP levels with echocardiographic and clinical data. All parameters of LV function on echocardiography significantly correlated with plasma BNP levels except RWT. LVMI had the highest correlation with plasma BNP level, followed by LVEF (LVMI, ρ=0.306, P<0.0001 and LVEF, ρ=−0.290, P<0.0001, respectively). Plasma BNP levels were lower with concentric remodeling/hypertrophy than with eccentric hypertrophy (P=0.0001) and marginally lower (P=0.045) with concentric remodeling than with concentric hypertrophy (Figure S1). Besides the cardiac hemodynamic parameters, plasma levels of C-reactive protein (CRP), creatinine, albumin, and uric acid and the estimated glomerular filtration rate (eGFR) had a significant association with plasma BNP levels (P<0.0001, P<0.0001, P<0.0001, P=0.002, and P<0.0001, respectively). Multivariable linear regression analysis revealed that LVMI, LVEF, plasma albumin, CRP, and uric acid were significant predictors of plasma BNP in that order (P<0.001, P<0.001, P=0.009, P=0.012, and P=0.018, respectively) in all the study subjects (Table 4).

Table 3. Correlation of Echocardiographic and Clinical Parameters With Plasma BNP Levels in HF Patients

Variable	Rho	P value
LVMI	0.306	<0.0001
EF	−0.290	<0.0001
IVST	0.180	<0.0001
LAD	0.172	<0.0001
LVDd	0.172	<0.0001
PWT	0.160	0.0001
E/e’	0.155	0.0001
e’	−0.097	0.0183
SVI	−0.093	0.0453
RWT	−0.022	0.60
CRP	0.296	<0.0001
Creatinine	0.232	<0.0001
Albumin	−0.230	<0.0001
eGFR	−0.211	<0.0001
UA	0.168	0.0022

UA, uric acid. Other abbreviations as in Tables 1,2.

Table 4. Multiple Linear Regression Analysis for Plasma BNP in HF Patients

Ln BNP	Adj R2=0.362
	Coeff.	t	P value
Ln LVMI	0.788	4.59	<0.001
Ln EF	−0.732	−4.30	<0.001
Ln albumin	−0.748	−2.66	0.009
Ln CRP	0.079	2.55	0.012
Ln UA	0.409	2.38	0.018
Ln eGFR	−0.184	−1.37	0.17
Ln E/e’	0.164	0.95	0.34

Coeff., coefficient; HF, heart failure; Ln, logarithmic transformation. Other abbreviations as in Tables 1,2.

Comparison of Clinical and Echocardiographic Characteristics Between Patients Aged ≤80 and >80 in the HFpEF Group

Table 5 compares the clinical characteristics of HFpEF patients between those aged ≤80 years and those >80 years (very elderly). Body mass index (BMI), hemoglobin, red blood cells, albumin, and eGFR were lower (P<0.0001, P<0.0001, P<0.0001, P=0.0002, and P=0.0063, respectively), while the proportion of women, systolic blood pressure and pulse pressure were all higher (P<0.001, P=0.0471, and P=0.0015, respectively) in the very elderly than in the ≤80 years HFpEF patients. Thus, the very elderly HFpEF patients were predominantly women, lean, anemic, and had increased pulse pressure or aortic stiffness, low plasma albumin, and reduced kidney function associated with less prevalence of comorbidities such as obesity/diabetes mellitus or dyslipidemia as compared with those aged ≤80 years. Table 6 compares the echocardiographic parameters of the very elderly HFpEF patients with those of the HFpEF patients aged ≤80 years. LVDd, IVST, PWT, e’, LVMI, and LAD were lower (P<0.0001, P<0.0001, P=0.0051, P<0.0001, P=0.0176, and P=0.0254, respectively) and RWT tended to be higher (P=0.052). Accordingly, the proportion of concentric remodeling/hypertrophy was higher and that of eccentric hypertrophy much lower (P=0.013 and P=0.009, respectively) in the very elderly HFpEF than in HFpEF patients aged ≤80 years. The very elderly HFpEF patients therefore had smaller and more concentrically remodeled hearts with stiffer aortas and LVs than the HFpEF patients aged ≤80 years with similarly elevated BNP levels.

Table 5. Comparison of Clinical Characteristics of HFpEF Patients Aged ≤80 or >80 Years

Variable	Age ≤80 (n=186)	Age >80 (n=282)	P value
Age (years)	72±7 (44–80)	88±5 (81–101)	<0.0001
Sex (women, %)	98 (53)	212 (75)	<0.001
BMI (kg/m2)	22.6 (19.5, 26.0)	20.4 (17.8, 23.0)	<0.0001
Systolic BP (mmHg)	129±23	133±22	0.0471
Diastolic BP (mmHg)	72±13	71±14	0.1957
Pulse BP (mmHg)	56±17	62±19	0.0015
Heart rate (beats/min)	75±17	72±14	0.2700
BNP (pg/mL)	206 (129, 344)	195 (135, 303)	0.6949
Hemoglobin (g/dL)	12.0±2.0	11.1±1.9	<0.0001
Red blood cells (×104/mL)	385 (343, 427)	354 (311, 391)	<0.0001
Creatinine (mg/dL)	0.9 (0.7, 1.2)	0.9 (0.7, 1.1)	0.5826
UA (mg/dL)	5.6 (4.7, 6.6)	5.4 (4.4, 6.4)	0.2167
Albumin (g/dl)	3.7 (3.5, 4.0)	3.6 (3.3, 3.9)	0.0002
Blood sugar (mg/dL)	113 (96, 135)	118 (99, 141)	0.2835
eGFR (mL/min/1.73 m2)	57 (41, 71)	50 (39, 62)	0.0063
White blood cells (×102/mL)	59 (47, 75)	58 (47, 77)	0.9066
Platelets (×104/mL)	18.2 (14.4, 23.6)	17.5 (13.5, 21.4)	0.0764
CRP (mg/L)	2.2 (0.6, 9.1)	2.6 (0.8, 14.9)	0.1117
Hypertension (%)	77	82	0.184
Old myocardial infarction (%)	18	16	0.580
Dyslipidemia (%)	48	30	<0.001
Diabetes mellitus (%)	57	36	<0.001
Atrial fibrillation (%)	42	28	0.002
CKD (eGFR <30) (%)	14	15	0.802
Obesity (BMI ≥25) (%)	32	14	<0.001
ACEI/ARB (%)	62	56	0.151
β-blocker (%)	47	27	<0.001
MR antagonist (%)	16	18	0.545
Diuretic (%)	34	42	0.071
Calcium-channel blocker (%)	49	45	0.368

Abbreviations as in Tables 1,3.

Table 6. Comparison of Echocardiographic Data for HFpEF Patients Aged ≤80 or >80 Years

Variable (normal range)	Age ≤80 (n=186)	Age >80 (n=282)	P value
LVDd (mm) (36–52)	44 (39, 48)	41 (37, 45)	<0.0001
LVMI (g/m2) (43–115)	125 (109, 152)	118 (100, 136)	0.0176
RWT (<0.42)	0.51 (0.46, 0.60)	0.53 (0.48, 0.61)	0.0522
Concentric remodeling (%)	82.1	91.0	0.013
Eccentric hypertrophy (%)	13.8	5.7	0.009
EF (%) (50–80)	66 (60, 73)	66 (61, 73)	0.5078
SVI (mL/m2)	38 (32, 45)	36 (29, 44)	0.2308
LAD (mm) (27–45)	40 (33, 45)	37 (32, 43)	0.0254
e’	4.7 (3.8, 5.9)	4.1 (3.4, 5.0)	<0.0001
E/e’ (<8)	18.3 (16.4, 21.1)	18.4 (16.5, 21.8)	0.2979
IVST (mm) (8–11)	12.5 (11.0, 13.5)	11.7 (10.3, 12.7)	<0.0001
PWT (mm) (8–11)	11.2 (10.3, 12.6)	10.9 (10.1, 12.1)	0.0051

Concentric remodeling includes concentric remodeling/hypertrophy. Abbreviations as in Tables 1,2.

Discussion

In humans BNP is produced from the LV in proportion to the severity of LV dysfunction.^1–3 Accordingly, the plasma level of BNP has been widely used as a marker of the diagnosis, severity, and prognosis of HF.^2–5,7 The present study showed that lower plasma BNP levels were more prevalent among the aged, particularly women, and were associated with higher systolic blood pressure and pulse pressure in HFpEF patients than in those with HFrEF. These findings are consistent with previous studies.^7–9,11

The previous studies showed that HFpEF was characteristically associated with metabolic syndrome including overweight/obesity, hypertension, and type 2 diabetes mellitus, together with other comorbidities as compared with HFrEF.^7–9 Lower BNP levels in HFpEF were thus explained by the increased visceral adipose tissue and associated chronic inflammation, which lead to decreased production and increased clearance of the hormone.^7–9

The present study, however, showed that the HFpEF patients were rather lean and more elderly, with a mean age of 81 years, and the incidence of HFpEF in HF was much higher (80.1 %) as compared with previous studies.^7–9 Comparison between the HFpEF patients aged >80 and those ≤80 years of age revealed that the very elderly HFpEF patients had wider pulse pressure or stiffer aortas, smaller hearts with concentric remodeling/hypertrophy and diastolic dysfunction, and lower BMI than those aged ≤80 years, indicating that aging per se exhibits hemodynamic and geometric characteristics of HFpEF and is therefore deeply involved in the pathogenesis of HFpEF. This line of thinking is supported by the recent parabiosis experiments in which hearts of young animals acquired HFpEF-like features when exposed to blood from old animals and hearts of old animals reversed their HFpEF-like features when exposed to the blood of young animals.^9,12

Aortic stiffness increases with age and leads to elevated systolic blood and pulse pressures, which impose systolic overload, because of augmented wave reflection, on the LV, resulting in diastolic dysfunction^13–17 and concentric remodeling/hypertrophy with increased wall thickness and relatively little change in volume.^15–20 In the present study, the HFpEF patients had lower LVDd and LVMI but higher RWT, displaying predominantly concentric remodeling/hypertrophy with a similar increase in E/e’ or LV end-diastolic pressure as compared with HFrEF patients. LV diastolic wall stress, which is proportional to pressure and cavity radius and inverse to wall thickness according to the Laplace law,¹⁵ is therefore considered to be lower in patients with HFpEF because of the presence of concentric remodeling/hypertrophy compared with HFrEF patients who are predominantly associated with eccentric hypertrophy. It is thus reasonable to postulate that lower plasma BNP levels in HFpEF are causally associated with lower LV diastolic wall stress. Indeed, the multivariable analysis revealed that LVMI incorporating LVDd and LV wall thickness was the most significant predictor of plasma BNP levels in the present study. Experimental studies have shown that stretching of cardiomyocytes stimulates BNP production by way of transient receptor potential channel 6 (TRPC6), which increases intracellular Ca²⁺ and thereby activates the calcineurin/nuclear factor of activated T-cells and calcium/calmodulin-dependent protein kinase II (CaMKII) signaling pathways, leading to cardiac hypertrophy.^21,22 BNP in turn attenuates TRPC6 activity and thereby suppresses cardiac hypertrophy through the guanylyl cyclase (GC)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway, thus constituting a negative feedback loop.^21–24

The present study also showed that chronic systemic inflammation and oxidative stress, as reflected by increased plasma CRP, decreased albumin and increased uric acid levels, also are associated with BNP, in agreement with our previous study.²⁵ It is thus possible that the elevation in BNP levels may be a manifestation of aging- and/or comorbidity-associated chronic systemic inflammation and oxidative stress²⁶ in patients with HFpEF (Figure S2). Paulus and coworkers recently proposed a new paradigm for the development of HFpEF, identifying a systemic inflammation induced by comorbidities as leading to coronary microvascular endothelial inflammation and subsequent LV concentric remodeling/hypertrophy and stiffness.^9,27 These lines of thinking are summarized and illustrated in Figure S3.

Clinical Implications

Patients with HFpEF have myocardial hypertrophy, interstitial fibrosis and LV diastolic stiffening.^6–9 Cardiomyocyte stiffening and relaxation are mainly determined by the elastic sarcomeric protein titin,^28,29 and cGMP-PKG activity derived from either nitric oxide (NO) or natriuretic peptides improves cardiomyocyte stiffness and relaxation by phosphorylation of titin and troponin I.^28–32 However, NO-derived myocardial cGMP-PKG activity is impaired and reduced by aging- and comorbidity-dependent chronic inflammation in HFpEF patients.^28–32 Reduced cGMP-PKG activity contributes to increased arterial stiffness and impaired relaxation, leading to increased LV systolic overload and concentric remodeling/hypertrophy and increased stiffness.^{6–9,28–32} BNP shows direct antihypertrophic and antifibrotic as well as antihypertensive effects.^4,7,22–24 It is therefore likely that BNP production is stimulated in response to LV concentric remodeling/hypertrophy and increased stiffness to compensate for the reduced NO-derived myocardial cGMP-PKG activity, but its effect is insufficient and reduced in HFpEF as compared with HFrEF.^{7–9,32–35} Targeting cGMP-PKG activity may thus be a novel way of treating and preventing HFpEF, particularly in view of the fact that medications with proven benefit in HFrEF have failed to have similar effects in HFpEF.^6–9 However, sildenafil, an inhibitor of phosphodiesterase 5 (PDE5), which predominantly degrades NO-derived cGMP, failed to ameliorate HFpEF,³⁶ probably because PDE5 as well as NO-derived cGMP is reduced.^28–33 It is interesting to note in this connection that an inhibitor of neprilysin, which degrades natriuretic peptides, including BNP, had beneficial effects on HFpEF³⁷ and that PDE 9A rather than PDE5 degrades natriuretic peptides and its inhibition protects against HFpEF independent of NO-derived cGMP activity.³⁸ Suppression of chronic systemic inflammation and increased systolic blood pressure together with pulse pressure are therefore expected to be effective for HFpEF particularly in those with predominant or isolated systolic hypertension. However, increased systolic pressure and pulse pressure, and chronic systemic inflammation are intrinsically related to aging^{13,16,26,34,35} and it is challenging to suppress or delay the progress of aging itself. It is interesting to note in this connection that intensive systolic blood pressure control prevented the development of major cardiovascular events, particularly HF in older patients with hypertension, as compared with standard blood pressure control, in very recent trials.^39,40 Caloric restriction and exercise training have been reported to delay aging and may thus be useful for the management of HFpEF as well.^7–9,41

Study Limitations

We did not have invasive hemodynamic data to estimate arterial and pressure LV pressures. However, the non-invasive echocardiographic pressure assessments have been validated and are well accepted in the literature.^10,42 LVMI assessed using 2D images may not have been accurate in the case of non-uniform LV wall thickness. However, only the 3D technique directly measures myocardial volume, hence LVMI, but this technique is currently limited and insufficient for reference values.⁴³ The study patients were Japanese, the most aged population in the world, and the results may not necessarily be applicable to other ethnic or racial populations. The study was cross-sectional and does not allow for causality between LV concentric remodeling/hypertrophy and plasma BNP levels.

Conclusions

Plasma BNP levels were lower and associated with predominantly LV concentric remodeling/hypertrophy, presumably derived from age-related higher systolic and pulse pressures or aortic stiffness in the HFpEF patients than in the HFrEF patients, who were associated predominantly with eccentric hypertrophy. The results imply that LV concentric remodeling/hypertrophy and hence less end-diastolic wall stress stimulates less BNP production in HFpEF as compared with HFrEF. These findings strongly suggest that the pathogenesis and hence management of HFpEF may be distinct from those of HFrEF.

Acknowledgments

We thank Ms. Yoshimi Tokunaga at the clinical laboratory of our institution for measuring laboratory data and Mrs. Emi Tateyama for secretarial assistance.

Disclosures

There are no relationships with industry and no conflicts of interest regarding this study.

Sources of Funding

This study was supported in part by the Japan Heart Foundation, Tokyo, and the Japan Vascular Disease Research Foundation, Kyoto, Japan.

Supplementary Files

Supplementary File 1

Figure S1. Comparison of plasma BNP levels between LV geometric types in heart failure patients.

Figure S2. Comparison of the distribution of plasma BNP levels in the HFpEF and HFrEF groups.

Figure S3. Relationship among aging, chronic systemic inflammation, systolic blood pressure, concentric LV remodeling/hypertrophy, HFpEF, and BNP.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-16-1282

References

• 1.   Mukoyama M, Nakao K, Hosoda K, Suga S, Saito Y, Ogawa Y, et al. Brain natriuretic peptide as a novel cardiac hormone in humans: Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest 1991; 87: 1402–1412.
• 2.   Yoshimura M, Yasue H, Okumura K, Ogawa H, Jougasaki M, Mukoyama M, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure. Circulation 1993; 87: 464–469.
• 3.   Yasue H, Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994; 90: 195–203.
• 4.   Grantham JA, Burnett JC Jr. BNP: Increasing importance in the pathophysiology and diagnosis of congestive heart failure. Circulation 1997; 96: 388–390.
• 5.   McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: 1787–1847.
• 6.   Sakata Y, Ohtani T, Takeda Y, Yamamoto K, Mano T. Left ventricular stiffening as therapeutic target for heart failure with preserved ejection fraction. Circ J 2013; 77: 886–892.
• 7.   Sharma K, Kass DA. Heart failure with preserved ejection fraction: Mechanisms, clinical features, and therapies. Res 2014; 115: 79–96.
• 8.   Senni M, Paulus WJ, Gavazzi A, Fraser AG, Díez J, Solomon SD, et al. New strategies for heart failure with preserved ejection fraction: The importance of targeted therapies for heart failure phenotypes. Eur Heart J 2014; 35: 2797–2815.
• 9.   Shah SJ, Kitzman DW, Borlaug BA, van Heerebeek L, Zile MR, Kass DA, et al. Phenotype-specific treatment of heart failure with preserved ejection fraction: A multiorgan roadmap. Circulation 2016; 134: 73–90.
• 10.   Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: A report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18: 1440–1463.
• 11.   Yamaguchi H, Yoshida J, Yamamoto K, Sakata Y, Mano T, Akehi N, et al. Elevation of plasma brain natriuretic peptide is a hallmark of diastolic heart failure independent of ventricular hypertrophy. J Am Coll Cardiol 2004; 43: 55–60.
• 12.   Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 2013; 153: 828–839.
• 13.   Mitchell GF. Arterial stiffness and hypertension: Chicken or egg? Hypertension 2014; 64: 210–214.
• 14.   Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin 2008; 4: 23–36.
• 15.   Grossman W, Paulus WJ. Myocardial stress and hypertrophy: A complex interface between biophysics and cardiac remodeling. J Clin Invest 2013; 1 23: 3701–3703.
• 16.   Sun Z. Aging, arterial stiffness, and hypertension. Hypertension 2015; 65: 252–256.
• 17.   Toischer K, Rokita AG, Unsöld B, Zhu W, Kararigas G, Sossalla S, et al. Differential cardiac remodeling in preload versus afterload. Circulation 2010; 122: 993–1003.
• 18.   Kehat I, Davis J, Tiburcy M, Accornero F, Saba-El-Leil MK, Maillet M, et al. Extracellular signal-regulated kinases 1 and 2 regulate the balance between eccentric and concentric cardiac growth. Circ Res 2011; 108: 176–183.
• 19.   van Berlo JH, Maillet M, Molkentin JD. Signaling effectors underlying pathologic growth and remodeling of the heart. J Clin Invest 2013; 123: 37–45.
• 20.   Schiattarella GG, Hill JA. Inhibition of hypertrophy is a good therapeutic strategy in ventricular pressure overload. Circulation 2015; 131: 1435–1447.
• 21.   Kuwahara K, Wang Y, McAnally J, Richardson JA, Bassel-Duby R, Hill JA, et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J Clin Invest 2006; 116: 3114–3126.
• 22.   Kinoshita H, Kuwahara K, Nishida M, Jian Z, Rong X, Kiyonaka S, et al. Inhibition of TRPC6 channel activity contributes to the antihypertrophic effects of natriuretic peptides-guanylyl cyclase-A signaling in the heart. Circ Res 2010; 106: 1849–1860.
• 23.   Ogawa Y, Tamura N, Chusho H, Nakao K. Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart. Can J Physiol Pharmacol 2001; 79: 723–729.
• 24.   Li Y, Kishimoto I, Saito Y, Harada M, Kuwahara K, Izumi T, et al. Guanylyl cyclase-A inhibits angiotensin II type 1A receptor-mediated cardiac remodeling, an endogenous protective mechanism in the heart. Circulation 2002; 106: 1722–1728.
• 25.   Harada E, Nakagawa O, Yoshimura M, Harada M, Nakagawa M, Mizuno Y, et al. Effect of interleukin-1 beta on cardiac hypertrophy and production of natriuretic peptides in rat cardiocyte culture. J Mol Cell Cardiol 1999; 31: 1997–2006.
• 26.   Franceschi C1, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007; 128: 92–105.
• 27.   Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: Comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62: 263–271.
• 28.   Linke WA, Hamdani N. Gigantic business: Titin properties and function through thick and thin. Circ Res 2014; 114: 1052–1068.
• 29.   Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, et al. Myocardial stiffness in patients with heart failure and a preserved ejection fraction: Contributions of collagen and titin. Circulation 2015; 131: 1247–1259.
• 30.   Takimoto E. Cyclic GMP-dependent signaling in cardiac myocytes. Circ J 2012; 76: 1819–1825.
• 31.   van Heerebeek L, Hamdani N, Falcão-Pires I, et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 2012; 126: 830–839.
• 32.   Rainer PP, Kass DA. Old dog, new tricks: Novel cardiac targets and stress regulation by protein kinase G. Cardiovasc Res 2016; 111: 154–162.
• 33.   Greene SJ, Gheorghiade M, Borlaug BA, Pieske B, Vaduganathan M, Burnett JC Jr, et al. The cGMP signaling pathway as a therapeutic target in heart failure with preserved ejection fraction. J Am Heart Assoc 2013; 2: e000536.
• 34.   Loffredo FS, Nikolova AP, Pancoast JR, Lee RT. Heart failure with preserved ejection fraction: Molecular pathways of the aging myocardium. Circ Res 2014; 115: 97–107.
• 35.   Upadhya B, Taffet GE, Cheng CP, Kitzman DW. Heart failure with preserved ejection fraction in the elderly: Scope of the problem. J Mol Cell Cardiol 2015; 83: 73–87.
• 36.   Redfield MM, Chen HH, Borlaug BA, Semigran MJ, Lee KL, Lewis G, et al; RELAX Trial. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: A randomized clinical trial. JAMA 2013; 309: 1268–1277.
• 37.   Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al; Prospective comparison of ARNI with ARB on management of heart failure with preserved ejection fraction (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: A phase 2 double-blind randomised controlled trial. Lancet 2012; 380: 1387–1395.
• 38.   Lee DI, Zhu G, Sasaki T, Cho GS, Hamdani N, Holewinski R, et al. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 2015; 519: 472–476.
• 39.   SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015; 373: 2103–2116.
• 40.   Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, et al. intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: A randomized clinical trial. JAMA 2016; 315: 2673–2682.
• 41.   Kitzman DW, Brubaker P, Morgan T, Haykowsky M, Hundley G, Kraus WE, et al. effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: A randomized clinical trial. JAMA 2016; 315: 36–46.
• 42.   Little WC, Oh JK. Echocardiographic evaluation of diastolic function can be used to guide clinical care. Circulation 2009; 120: 802–809.
• 43.   Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015; 16: 233–270.