Effects of Sacubitril/Valsartan on Myocardial Tissue in Heart Failure With Left Ventricular Ejection Fraction Below 50%

Abstract

Background: The effects of sacubitril/valsartan (angiotensin receptor–neprilysin inhibitor [ARNI]) on myocardial tissue in heart failure (HF) with left ventricular ejection fraction (LVEF) <50% remain unclear.

Methods and Results: Sixty-four HF outpatients with LVEF <50% were randomized to ARNI (switching from an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker [ACEi/ARB] to ARNI) or control (continuing with ACEi/ARB). Left ventricular (LV) structure and myocardial tissue, including changes in LV extracellular volume fraction (ECV), were evaluated before and after the 9-month program using cardiac magnetic resonance imaging. The primary endpoint was changes in ECV. Secondary endpoints were changes in LVEF, LV volume and mass, and extra- and intracellular mass. Fifty-nine patients completed the 9-month intervention. ARNI decreased systolic blood pressure from the first month. The ARNI group showed significant reductions in LV volume, LV mass, and extra- and intracellular mass from baseline to 9 months, but there was no change in LVEF, or in ECV (31.6±5.0% vs. 31.9±5.0%, respectively; P=0.795). In the control group, there was no change in systolic blood pressure, LV volume, LV mass, ECV, or extra- and intracellular mass. There was no significant difference in the change in ECV between the ARNI and control groups (0.3±5.1% vs. 1.2±4.1%, respectively; P=0.461), whereas the change in extracellular mass was greater in the ARNI group (P=0.025).

Conclusions: ARNI reduced LV volume and mass, resulting from decreases in both extra- and intracellular mass, without changing ECV. This suggests ARNI has potential to improve LV tissue characteristics in HF patients with LVEF <50%.

The prevalence of heart failure (HF) is increasing and the 1-year mortality rate is high, at approximately 7%.¹ Myocardial structural changes, including fibrosis, are closely related to cardiac vulnerability.² Interstitial fibrosis in the left ventricle (LV) is partially reversible.³ The extent of fibrosis appears to be associated with HF hospitalization and mortality.⁴

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is one of the key drugs in guideline-directed medical therapy for HF with reduced ejection fraction (HFrEF), and was shown to successfully reduce cardiovascular and HF deaths in HFrEF patients in the PARADIGM-HF trial.^5,6 Current guidelines recommend switching HFrEF patients to ARNI.⁷ In addition, ARNI has recently been reported to reduce cardiovascular events among HF patients with a mildly reduced LV ejection fraction (LVEF) and those with HFrEF.⁸ ARNI has been reported to attenuate the process of adverse LV remodeling, reduce LV mass, and improve LVEF in hypertensive patients⁹ and HFrEF patients.¹⁰ However, the beneficial effects of ARNI on the properties of myocardial tissue have not been assessed pathologically or non-invasively.

Contrast-enhanced cardiac magnetic resonance (CMR) imaging is an excellent non-invasive tool for evaluating the properties of myocardial tissue and the extracellular space using non-enhanced native T1 values and the extracellular volume fraction (ECV).¹¹ Treatment of HF with angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs), coupled with β-blockers and mineralocorticoid receptor antagonists, induces favorable LV reverse remodeling and reductions in LV myocardial fibrosis and ECV.¹² Recently, using CMR, we reported on changes in the characteristics of myocardial tissue in patients with recent-onset idiopathic dilated cardiomyopathy (DCM) treated with ACEi/ARBs.¹³ Patients exhibited increases in LVEF and decreases in LV volumes during a 9-month follow-up, and reductions in native T1 values were correlated with increases in LVEF values.¹³ In addition, ECV decreased in some patients who underwent repeated ECV measurements using contrast medium.¹³ Due to its clinical effectiveness, ARNI for HF is expected to be more effective than ACEi/ARBs for LV myocardial fibrosis and ECV.

In the present study we investigated the effects of ARNI in HF patients with LVEF <50% using cine CMR and native T1 and ECV mapping. We examined the structure of the LV and myocardial tissue properties based on ECV and native T1 before and after a 9-month treatment period with ARNI in stable HF outpatients who had LVEF <50% during outpatient visits.

Methods

Study Design

This was a prospective multicenter 2-arm randomized open-label trial (masking not used) conducted in Mie University Hospital and Matsusaka Central General Hospital from September 2021 to December 2023. The Clinical Research Support Center of Mie University performed random assignments, and the study was registered with the Japan Registry of Clinical Trials (jRCT1041210066). The Ethics Committee of Mie University Hospital approved the study protocol (No. CRB4180006). The study was performed in accordance with the Declaration of Helsinki, and all patients provided written informed consent.

Participants

Patients with chronic HF who satisfied the following conditions were eligible for inclusion in the study: (1) HF symptoms (New York Heart Association [NYHA] Class I–III); (2) LVEF <50% by echocardiography or CMR performed within the past 3 months; (3) uptitration of HF medications for at least 4 weeks; and (4) B-type natriuretic peptide (BNP) level ≥18.4 pg/mL or N-terminal pro BNP (NT-proBNP) level ≥100 pg/mL within the past 3 months. Exclusion criteria were symptomatic hypotension and/or systolic blood pressure <90 mmHg, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m², acute coronary syndrome, stroke, cardiovascular surgery, carotid artery surgery, or percutaneous coronary intervention within the past 3 months, HF hospitalization within the past 6 months, persistent/permanent atrial fibrillation, implantable cardiac devices, cardiac amyloidosis, severe valvular heart disease, serum potassium >5.2 mmol/L, history of angioedema, hypersensitivity to HF medications, unstable angina, liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥100 IU/L), and pregnancy.

Intervention

This study included 6 visits over a 9-month period. In the baseline (pretreatment) visit, all patients underwent clinical assessments, anthropometric measurements, blood tests, and CMR. Patients with HF were assigned 1 : 1 to either a sacubitril/valsartan (ARNI) group (target dose 200 mg twice daily) or conventional treatment (control) group (continued ACEi/ARB) for 9 months. Sacubitril/valsartan was started at 50 mg twice daily. One, 2, 3, and 6 months after randomization, patients visited their physicians for an interview and blood tests. Uptitrations to the target dose were attempted after randomization depending on symptoms associated with low blood pressure, renal function, and serum potassium levels. A block randomization process was used with age (≥65 or <65 years) and sex as adjusting factors to ensure a balanced distribution.

CMR Imaging

CMR studies were performed using a 3.0-T magnetic resonance scanner (Ingenia 3.0T; Philips Healthcare, Best, Netherlands) equipped with dS coils. The CMR study protocol included cine CMR, T1 mapping before contrast, late gadolinium enhancement (LGE) CMR, and T1 mapping by modified Look-Locker inversion recovery (MOLLI) after contrast.^13–15 Cine CMR images were acquired with a retrospective electrocardiogram (ECG) gating, segmented steady-state free precession (SSFP) technique in the short-axis imaging plane covering the entire LV, and 2- and 4-chamber long-axis imaging planes.^13,15,16

T1 mapping was performed using an SSFP single breath hold using a MOLLI 5s(3s) 3s acquisition scheme on 3 LV short-axes (base, mid-ventricle, and apex) and 2 long-axis imaging planes (repetition time/echo time=2.6/1.1 ms, flip angle=35°, field of view=300×330 mm, acquisition matrix=176×141, reconstruction matrix=352×352, SENSE factor=2, slice thickness=10 mm). LGE magnetic resonance images were acquired in the LV short-axis planes corresponding to the short-axis cine imaging planes using an inversion recovery 3D gradient echo sequence around 10 min after the intravenous administration of gadoterate meglumine (Gd-DOTA; Magnescope^®; Guerbet Japan KK, Tokyo, Japan) at a dose of 0.15 mmol/kg. Post-contrast MOLLI T1 mapping was repeated 15 min after contrast injection for LGE magnetic resonance imaging using identical settings as for the precontrast T1 mapping.

CMR Analysis

CMR images were analyzed using the cvi42 CMR analysis software (Circle Cardiovascular Imaging Inc., Calgary, Canada) by an experienced radiologist (T. Kokawa; 6 years of CMR experience) who was blinded to the subject’s clinical information. On the short-axis cine CMR images, the epi- and endocardial borders of the LV wall were manually traced at end-diastole and end-systole to measure the LV mass and LV end-diastolic and end-systolic volumes. Left atrial maximum volume was measured using the area-length method. LV mass was calculated as the sum of myocardial areas multiplied by slice thickness and the density (1.05 g/mL) of myocardial tissue.¹⁷

Pixel-wise T1 maps were generated by fitting pixels to the following equations:

s(t) = a − b exp(−t / T1*)

T1 = T1*(b / a − 1)

where a and b are constants, t is time, and s(t) is signal intensity at time t. To calculate the ECV, averaged pre- and post-contrast T1 values of the LV blood pool were obtained by manually placing regions of interest (ROI) in the center of the blood pool. Then, a pixel-wise ECV map was generated based on combined native and post-contrast T1 maps using the following formula:

ECV = (∆R1 myocardium / ∆R1blood) × (1 − hematocrit)

where R1=1/T1.¹⁸ Native T1 and ECV were measured as averages in ROIs drawn as large as possible (to avoid contamination by the blood pool signal and artifacts due to misregistration) on a single midventricular slice of the corresponding native T1 and ECV maps. To minimize blood pool contamination in ROI measurements, the raw image series for T1 mapping and the T1 maps before and after contrast injection were carefully examined. When apparent misregistration was observed, it was corrected using contour-based registration.¹⁹ For patients with a history of previous myocardial infarction, the affected myocardial area was excluded from the analysis.

In addition, we calculated LV extracellular mass (ECM), which is potentially linked to worsening myocardial fibrosis and LV dysfunction, and LV intracellular mass (ICM) using the following previously reported¹⁸ equations:

ECM = LV mass × ECV / 100

ICM = LV mass − ECM

Blood Tests and Biomarkers

Complete blood counts, biochemistry, and plasma natriuretic peptides (A-type natriuretic peptide [ANP], BNP, and NT-proBNP) were evaluated. Details of the myocardial fibrosis markers galectin-3 and Suppression of Tumorigenicity 2 (ST2), were collected at baseline and after 9 months of treatment.^20,21

Endpoints

The primary endpoint in this study was the between-group change in ECV from baseline to 9 months. Secondary endpoints were LV end-diastolic and end-systolic volumes, LVEF, LV mass, ECM, ICM, and native T1 values. Between-group changes during the 9 months were also compared between the 2 groups. Office blood pressure and blood data were sampled at the time of registration, as well as 1, 2, 3, 6, and 9 months later. Subgroups were created based on the etiology of HF (ischemic or idiopathic DCM) for analyses of primary and secondary endpoints.

Sample Size Calculation

In our previous study on HF patients with DCM,¹³ the level of decrease in ECV after optimal drug therapy was 2.3%, and the SD of the difference in the ECV decrease was 3.0%. In the present study, assuming an additional 2.3% decrease in ECV in the ARNI group (i.e., a mean [±SD] decrease of −4.6±3.0% in the ARNI group and −2.3±3.0% in the control group), the minimum number of cases required to detect a significant difference between groups with a probability of a Type II error at less than 20% (power=0.8) was 28 in each group, for a total of 56 patients. The number of patients was set at 66, with an expected dropout rate of approximately 15%.

Statistical Analysis

All analyses were performed using SPSS 24.0 (SPSS Japan Inc., Tokyo, Japan). Continuous variables are presented as the mean±SD in tables and the mean±SE in figures or as the median with interquartile range (IQR). Data were compared using unpaired t-tests or the non-parametric Mann-Whitney U test depending on data distribution. Categorical data are presented as percentages and were compared by the Chi-squared or Fisher exact test. A paired t-test, one-way repeated analysis of variance (ANOVA), or Friedman one-way repeated-measures ANOVA on ranks (non-parametric test) was used to evaluate repeated data within each group. If significant results were identified, a post hoc analysis was used for pre–post comparisons. Intra- and interobserver reproducibility were assessed in a randomly selected 20 participants using intraclass correlation coefficients (ICCs). Significance was set at P<0.05 (two-tailed).

Results

Baseline Characteristics

Sixty-seven patients were briefed about the study at an outpatient clinic and were assessed for their eligibility to participate. Sixty-four patients were ultimately randomized 1 : 1 to the ARNI and control groups (Figure 1). During the 9-month observation period, 5 patients dropped out. In the control group, 1 patient had active cancer. In the ARNI group, 1 patient was hospitalized for a percutaneous coronary intervention for exacerbated unstable angina. Another patient had symptomatic hypotension. A third patient voluntarily withdrew. In addition, 1 patient developed atrial fibrillation. Thus, 31 patients in the control group and 28 in the ARNI group underwent pre- and postintervention analyses.

Figure 1.

Study design. The initial dose of sacubitril/valsartan was 50 mg twice daily, and the dose was increased every month to 100 mg twice daily and 200 mg twice daily. AF, atrial fibrillation; ARNI, angiotensin receptor–neprilysin inhibitor; MRI, magnetic resonance imaging; UAP, unstable angina pectoris.

Baseline characteristics are summarized in Tables 1 and 2. Patients presented with the typical HFrEF phenotype, with reduced LVEF (34±9%), dilated LV, and elevated ECV (30.9±4.8%; the normal value at Mie University Hospital: 26.8±5.0%). At baseline, there were no significant differences between the ARNI and control groups in age, sex, body size, systolic or diastolic blood pressure, HF etiology, or medications, except for mineralocorticoid receptor antagonists, which were used by a significantly higher proportion of patients in the ARNI group. During follow-up, body weight remained unchanged in the ARNI group (66.9±15.4 vs. 66.5±16.1 kg; P=0.510), whereas a slight decrease was observed in the control group (63.6±10.2 vs. 62.1±10.8 kg; P=0.037).

Table 1.

Patient Characteristics Overall and According to Treatment Group

	All patients (n=59)	ARNI (n=28)	Control (n=31)	P value
Age (years)	68±12	70±11	68±13	0.617
≤65 years	16 (27)	8 (29)	8 (26)	0.811
>65 years	43 (73)	20 (71)	23 (74)	0.811
Male sex	52 (88)	25 (89)	27 (87)	1.000
Height (cm)	164±7	164±7	165±7	0.606
Body weight (kg)	65±13	67±15	64±10	0.339
BSA (m2)	1.71±0.17	1.72±0.20	1.70±0.15	0.593
BMI (kg/m2)	24±4	25±5	23±3	0.188
SBP (mmHg)	131±19	130±17	131±20	0.886
DBP (mmHg)	73±12	72±11	73±14	0.950
Heart rate (beats/min)	73±12	73±12	73±12	0.993
NYHA Class I/II (n)	27/32	14/14	13/18	0.535
Etiology
Dilated cardiomyopathy	19 (32)	8 (29)	11 (36)	0.570
Ischemic cardiomyopathy	37 (63)	18 (64)	19 (61)	0.812
Others	3 (5)	2 (7)	1 (3)	0.599
Comorbidities
Hypertension	41 (70)	21 (75)	20 (65)	0.382
Diabetes	21 (36)	10 (34)	11 (35)	0.985
HF hospitalization
6–12 months	5 (9)	4 (14)	1 (3)	0.180
≥12 months	36 (61)	16 (57)	20 (65)	0.562
Medication
ACEi	32 (54)	17 (61)	15 (60)	0.343
ARBs	27 (46)	11 (39)	16 (52)	0.343
β-blockers	56 (95)	27 (96)	29 (94)	1.000
MRAs	22 (37)	16 (57)	6 (19)	0.003
SGLT-2 inhibitors	15 (25)	7 (25)	8 (26)	0.943
Diuretics	29 (49)	15 (54)	14 (45)	0.519
Maximum dose of ARNI (mg/day)
50		1 (3)	N/A	–
100		7 (24)	N/A	–
200		6 (21)	N/A	–
400		14 (48)	N/A	–
Laboratory data
Hemoglobin (g/dL)	14.0±1.6	14.0±1.7	14.0±1.6	0.901
eGFR (mL/min/1.73 m2)	63.1±22.4	60.5±26.4	65.5±18.2	0.402
Serum creatinine (mg/dL)	1.0±0.3	1.1±0.4	0.9±0.2	0.117
BNP (pg/dL)	63.5 [35.8–123.9]	53.3 [39.4–123.7]	64.6 [35.6–132.2]	0.761
NT-proBNP (pg/dL)	511 [272–931]	575 [239–818]	510 [285–1,132]	0.808
ANP (pg/mL)	65.9 [42.6–130.8]	64.7 [36.0–85.4]	67.1 [47.3–144.2]	0.316

Unless indicated otherwise, values are the mean±SD, median [interquartile range], or n (%). ACEi, angiotensin-converting enzyme inhibitor; ANP, A-type natriuretic peptide; ARBs, angiotensin II receptor antagonists; ARNI, angiotensin receptor-neprilysin inhibitor; BMI, body mass index; BNP, B-type natriuretic peptide; BSA, body surface area; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; SGLT-2, sodium-glucose cotransporter 2.

Table 2.

Changes in Cardiac Magnetic Resonance Imaging Parameters According to Treatment Group

	ARNI			Control			P value
	Baseline	9 months	Change from baseline	Baseline	9 months	Change from baseline
LVEDV (mL)	192.8±64.0	181.0±58.6*	−11.7±21.9	202.1±64.8	205.2±70.7	3.1±31.3	0.041
LVESV (mL)	125.8±53.4	117.3±52.9*	−8.5±19.3	140.2±57.9	141.6±65.3	1.5±24.8	0.093
LVEF (%)	36.3±9.2	37.1±10.5	0.8±5.5	31.9±8.3	32.8±8.4	0.9±4.7	0.988
LV mass (g)	123.0±39.3	111.6±33.8*	−11.3±14.4	117.4±43.0	113.0±43.1	−4.4±15.8	0.086
ECV (%)	31.6±5.0	31.9±5.0	0.3±5.1	30.2±4.6	31.4±5.5	1.2±4.1	0.436
ECM (g)	38.9±14.8	35.4±11.5*	−3.6±7.3	35.2±12.4	35.4±14.5	0.2±5.3	0.025
ICM (g)	84.1±26.6	77.0±24.5*	−7.1±11.7	82.3±32.2	77.6±31.5	−4.7±13.8	0.480
Native T1 (ms)	1,278±42	1,282±47	4±43	1,283±65	1,274±66	−9±48	0.254
RVEDV (mL)	119.7±30.0	117.6±27.8	−2.1±15.7	131.3±43.3	128.9±36.5	−2.4±22.3	0.962
RVESV (mL)	53.8±17.0	54.4±17.8	0.6±22.3	70.1±35.5	67.0±28.2	−3.1±20.0	0.408
RVEF (%)	54.8±9.6	53.9±9.8	−0.9±6.6	48.1±11.4	49.4±9.9	1.2±7.0	0.228
LA volume (mL)	76.1±32.9	70.3±28.2	−5.7±18.9	71.3±24.1	70.2±22.4	−1.1±16.2	0.314

Values are the mean±SD. *P<0.05 compared with baseline. ARNI, angiotensin receptor-neprilysin inhibitor; ECM, extracellular mass; ECV, extracellular volume fraction; ICM, intracellular mass; LA, left atrial; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; RV, right ventricular; RVEDV, right ventricular end-diastolic volume; RVEF, right ventricular ejection fraction; RVESV, right ventricular end-systolic volume.

Safety

At the end of the study, 48% of patients receiving ARNI reached a daily dose of 400 mg, whereas others remained on lower doses (Table 1). Two patients in the ARNI group experienced temporary increases in creatinine, and 4 patients overall (3 ARNI, 1 control) experienced low systolic blood pressure (<90 mmHg). One patient in the control group developed a persistent cough. There were no cardiovascular deaths or rehospitalizations due to HF exacerbation.

Changes in Hemodynamics During the Study

Patients in the ARNI group exhibited a significant reduction in systolic blood pressure from the first month (131.8±18.6 vs. 123.6±15.0 mmHg, P=0.048) through to the sixth month (120.9±17.2 mmHg; P=0.002), an approximate 10-mmHg decrease from baseline (ANOVA P=0.004; Figure 2). In contrast, systolic blood pressure remained unchanged in the control group (ANOVA P=0.063). No changes in diastolic blood pressure (ANOVA P≥0.142) or heart rate (P≥0.578) were observed in either group.

Figure 2.

Blood pressure, B-type natriuretic peptide (BNP), N-terminal pro B-type natriuretic peptide (NT-proBNP), and A-type natriuretic peptide (ANP) in the angiotensin receptor–neprilysin inhibitor (ARNI) and control groups throughout the study. Data are presented as the mean±SE (blood pressure) or as box plots (BNP, NT-proBNP, ANP), where the boxes show the interquartile range, with the median value indicated by the horizontal line and whiskers showing the range. *P<0.05 vs. Baseline.

CMR Results

eGFR decreased in 1 patient in the ARNI group at 9 months and repeat CMR with no contrast medium was performed. Therefore, pre- and postintervention ECV, ECM, and ICM were compared in 27 patients in the ARNI group. As indicated in Table 2, there were no significant differences at baseline between the ARNI and control groups in LV end-diastolic volume (P=0.581), LV end-systolic volume (P=0.324), LVEF (P=0.063), LV mass (P=0.606), ECV (P=0.547), or native T1 values (P=0.712).

Over the 9-month ARNI treatment, significant decreases were observed in LV end-diastolic volume (6%; from 192.8±64.0 to 181.0±58.6 mL), LV end-systolic volume (7%; from 125.8±53.4 to 117.3±52.9 mL), and LV mass (9%; from 123.0±39.3 to 111.6±33.8 g). However, no changes were observed in LVEF (from 36.3±9.2 to 37.1±10.5%; P=0.429), with a change in LVEF of 0.83% (95% confidence interval [CI] –2.97%, 1.30%). Similarly, no changes were noted in ECV (31.6±5.0% vs. 31.9±5.0%; P=0.795) or native T1 (1,278±42 vs. 1,282±47 ms; P=0.646). In the control group, there were also no changes in LV end-diastolic and end-systolic volumes, LVEF, LV mass, ECV, or native T1 (P≥0.123; Table 2). Changes in ECV after the 9-month study period were not significantly different between the ARNI and control groups (0.3±5.1% vs. 1.2±4.1%, respectively; P=0.436; Table 2; Figure 3). No correlation was observed between the change in ANP and the change in left atrial volume in the ARNI group (R²=0.025, P=0.44).

Figure 3.

Absolute changes (∆) from baseline to 9 months in the angiotensin receptor-neprilysin inhibitor (ARNI) and control groups. Data are presented as the mean±SE. ECM, extracellular mass; ECV, extracellular volume fraction; LV, left ventricular.

Individual data for LV mass, ECM, and ICM are shown in Figure 4. Importantly, ECM decreased significantly in the ARNI group (38.9±14.8 vs. 35.4±11.5 g; P=0.017), but not in the control group (Table 2; Figure 4). The change in ECM was greater in the ARNI than control group (−3.6±7.3 vs. 0.2±5.3 g; P=0.025; Figure 3). ICM also decreased after the 9-month ARNI treatment, but remained unchanged in the control group.

Figure 4.

Individual changes from baseline to 9 months in the angiotensin receptor-neprilysin inhibitor (ARNI) and control groups in left ventricular (LV) mass, extracellular mass (ECM), and intracellular mass (ICM).

When 8 patients with an HF etiology of idiopathic DCM were analyzed, marked decreases in LV end-diastolic volume (185.9±42.0 vs. 159.7±45.5 mL; P=0.014) and LV mass (129.8±20.3 vs. 110.2±28.6 g, P=0.004) were observed from baseline to 9 months, with no change in ECV (31.0±3.8% vs. 30.9±4.4%; P=0.934; Table 3). Treatment with ARNI significantly decreased ECM and ICM (P≤0.048), and LVEF before and after the treatment program was 37.8±2.8% and 40.2±7.3%, respectively. In patients with DCM, a slight increase in LVEF of 2.4±6.3% (95% CI: −2.9%, 7.6%) was noted (P=0.322). In patients with ischemic cardiomyopathy, ARNI treatment had no effect on any CMR parameters.

Table 3.

Changes in Cardiac Magnetic Resonance Imaging Parameters in Patients With Idiopathic Dilated Cardiomyopathy or Ischemic Cardiomyopathy

	Idiopathic dilated cardiomyopathy			Ischemic cardiomyopathy
	Baseline	9 months	Change from baseline	Baseline	9 months	Change from baseline
LVEDV (mL)	185.9±42.0	159.7±45.5*	−26.2±22.7	194.2±74.9	189.1±65.0	−5.2±19.9
LVESV (mL)	117.0±27.8	97.5±36.9	−19.5±24.4	129.4±63.1	126.1±58.7	−3.3±16.2
LVEF (%)	37.8±2.8	40.2±7.3	2.4±6.3	35.2±10.8	35.3±11.2	0.0±5.4
LV mass (g)	129.8±20.3	110.2±28.6*	−19.6±13.4	117.4±45.3	109.9±37.0*	−7.4±13.9
ECV (%)	31.0±3.8	30.9±4.4	−0.1±2.6	32.0±5.6	32.2±5.3	0.2±6.0
ECM (g)	40.0±4.0	34.3±8.6*	−5.7±6.1	37.7±17.4	34.8±12.2	−2.9±8.0
ICM (g)	91.0±19.2	78.5±23.5*	−12.6±9.3	79.7±29.4	75.1±26.4	−4.6±12.3
Native T1 (ms)	1,291±25	1,278±29	−13±26	1,269±47	1,283±56	14±48
RVEDV (mL)	120.9±28.9	112.5±23.9*	−8.4±15.2	116.8±28.6	118.0±28.0	1.2±16.0
RVESV (mL)	55.2±22.4	50.5±18.1	−4.7±15.5	52.3±12.5	55.6±17.0	3.4±11.3
RVEF (%)	55.4±10.8	55.9±8.6	0.5±8.8	54.2±9.6	52.5±10.6	−1.7±6.0
LA volume (mL)	71.2±27.6	69.9±37.4*	−1.3±10.2	76.4±35.7	68.5±23.7	−7.9±22.6

Values are the mean±SD. *P<0.05 compared with baseline. Abbreviations as in Table 2.

The intra- and interobserver reproducibility for ECV, ECM, ICM, and native T1 demonstrated robust agreement, with intra-observer ICCs of 0.921, 0.918, 0.970, and 0.801, respectively, and interobserver ICCs of 0.947, 0.916, 0.970, and 0.833, respectively.

Laboratory Data and Blood Pressure

At the baseline, no differences were observed in hemoglobin, eGFR, BNP, NT-proBNP, or ANP between the 2 groups (Table 1). After the 9-month treatment with ARNI, NT-proBNP decreased significantly (ANOVA P=0.002), ANP increased significantly (ANOVA P<0.001), and BNP remained unchanged. When LV mass, ECM, ICM, and changes in ANP in the ARNI group were evaluated, no significant relationships were found between the change in ANP and either LV mass, ECM, or ICM (P≥0.301). In contrast, in the control group, there were no changes in NT-proBNP and BNP (ANOVA P≥0.088) and ANP levels were lower (ANOVA P=0.003; Figure 2).

At baseline, galectin-3 levels were slightly higher in the ARNI group than in the control group (10.3±5.6 vs. 8.1±3.2 ng/mL; P=0.09). There were no changes in galectin-3 levels after the 9-month treatment program in either group (P≥0.493) compared with baseline. At baseline, ST2 levels were similar in the ARNI and control groups (median 18.4 [IQR 13.8–22.8] vs. 28.4 [IQR 14.8–22.0] ng/mL, respectively; P=0.903). After the program, ST2 levels remained unchanged in the ARNI group, but decreased to a median of 14.9 ng/mL (IQR 12.1–21.9 ng/mL) in the control group (P=0.032).

Discussion

In the present study, we examined the structure and function of LV and myocardial tissue characteristics using CMR. Nine months of ARNI therapy significantly decreased LV volume, LV mass, and systolic blood pressure. Although LVEF and ECV remained unchanged, ECM and ICM were both significantly decreased by ARNI. These reductions in ECM and ICM resulted in ECV that overall remained unchanged. These results suggest that ARNI improved LV tissue characteristics and protected against further LV remodeling in HF patients with LVEF <50%, even those with a stable and mild symptomatic status.

Effects of ARNI on LV Volume, LVEF, and LV Mass

Cardiac remodeling is an important mechanism in the progression of HF. In the PARADIGM-HF study, ARNI reduced the risks of death and hospitalization due to HF in HF patients with LVEF ≤40%,⁵ suggesting that improvements in LVEF and LV reverse remodeling were associated with a decreased risk.²² In the MADIT-CRT study, the reverse remodeling effect was prominent in patients with a non-ischemic etiology.²³ ARNI more effectively induced LV reverse remodeling in patients with LVEF <30%, treated early after the onset of HF, non-ischemic HF, and no cardiac resynchronization therapy.²⁴ ARNI did not induce LV reverse remolding in patients with a previous history of myocardial infarction²⁵ when an LV end-systolic volume reduction ≥15% was defined as LV reverse remodeling. However, these studies primarily focused on clinical outcomes and did not investigate changes in myocardial tissue characteristics. To ensure the stability of the patient population and to avoid confounding factors, we enrolled stable outpatients who were free of HF hospitalization for at least 6 months. This design allowed us to explore how ARNI may affect underlying myocardial pathophysiology. In the present study, ARNI treatment successfully reduced LV end-systolic volume by 7%, but did not improve LVEF. However, a stratified analysis of DCM patients revealed a significant reduction in LV volume and mass with a potential increase in LVEF of 2.4±6.3% (95% CI −2.9%, 7.6%).

Impact of ARNI on Myocardial Tissue Characteristics and ECM

With the progression of myocardial fibrosis, the LV wall becomes stiffer, leading to increased LV stiffness and HF.²⁶ In evaluations of the myocardial and extracellular properties of the LV, CMR native T1 and ECV have been used as methods to detect ECM expansion and diffuse myocardial fibrosis.²⁷

In patients with recent-onset DCM who were admitted due to index HF, we found a greater reduction in LV end-systolic volume (by 42%) than in end-diastolic volume (by 26%),¹³ an improvement in LVEF, and shortened native T1 after optimal medical therapy.¹³ Simultaneously, LV mass decreased by 14%. Therefore, we hypothesized that ARNI increased LVEF and decreased ECV, native T1, and ECM. Contrary to our hypothesis, in chronic HF patients who had been treated with guideline-directed medical therapy, but not with ARNI, we found no favorable changes in ECV (30.3±3.6% vs. 31.2±4.1%; P=0.547) or native T1 (1,277±42 vs. 1,282±47 ms; P=0.646) after ARNI treatment, despite an apparent reduction in LV volume and mass. Representative data for a patient in the ARNI group are shown in Figure 5. The LV mass comprises the ECM and ICM. If both components decreased to a similar extent, an obvious change in ECV may not be detectable. Therefore, we analyzed not only LV mass, but also ECM and ICM in the present study. In the ARNI group, ECM decreased significantly by 3.6±7.3 g (from 39.0±15.0 to 35.4±11.5 g; P=0.017), along with a larger decrease in ICM of 7.1±11.7 g (from 84.1±26.6 to 77.0±24.5 g; P=0.004). The significant decrease in ECM may be explained by the attenuation of diffuse interstitial fibrosis by ARNI treatment, as shown in Figure 5, possibly through mechanisms including a lowered arterial afterload,²⁸ the stimulation of angiotensin AT₂ receptors via circulating angiotensin II,²⁹ and bradykinin-mediated suppression of myocardial fibrosis.³⁰

Figure 5.

Representative data for a patient in the angiotensin receptor-neprilysin inhibitor (ARNI) group showing a substantial decrease in the left ventricular (LV) volume, LV mass, intracellular mass (ICM) and extracellular mass (ECM) after ARNI treatment.

Changes in Myocardial Tissue Characteristics After Medical Therapy

We observed no changes in ECV or native T1 after the 9-month treatment with ARNI. We speculate that this stability may be attributed to a balanced reduction in both ICM and ECM, reflecting a comprehensive remodeling involving both cellular and extracellular components of the myocardium. Similar to our findings, Xu et al. reported improved LVEF and reverse remodeling in patients with DCM treated with guideline-directed therapy in follow-up CMR, but no change in ECV.³¹ Unchanged ECV in the follow-up was attributed to similar decreases in both the ECM mass and cell mass.³¹ In patients who underwent aortic valve replacement for severe aortic stenosis, Treibel et al. found that a reduction in LV afterload significantly reduced LV hypertrophy and ICM by 22%.³² After surgery, ECM decreased by 16% and ECV increased from 28.2±2.9% to 29.9±4.0% (P<0.001).³²

A significant reduction of ECV may be observed in patients with acute HF. This could be attributed to the fact that components of ECM such as myocardial edema, in addition to fibrosis, are more prominent. Our findings underscore the complexity of myocardial remodeling in chronic HF. Although stability in ECV during clinical practice has often been interpreted as no improvement in myocardial tissue characteristics, it may actually reflect a positive outcome in the context of decreased ICM in managing chronic HF. Thus, we propose that assessments of both ECV and ECM are required for an accurate evaluation of the effects of medications and/or procedures on the characteristics of the LV and myocardium.

Changes in Natriuretic Peptides and Markers of Fibrosis

We observed an increase in ANP levels and a decrease in NT-proBNP levels after 9 months, with reductions in both LV volume and mass, as well as in the ECM. Given that ANP is known to protect against myocardial fibrosis, we speculated that an increase in ANP may exert an inhibitory effect on LV myocardial fibrosis. However, analysis of changes revealed no correlation between changes in ANP and changes in ECM or between changes in ANP and changes in LV mass in the ARNI group. The results may differ if evaluations are performed in patients with recent-onset HF due to DCM. In addition, the observed tendency for decreased left atrial volume after ARNI may be influenced not only by changes in ANP but also by other hemodynamic effects of ARNI.

Although galectin-3 is not a myocardial-specific marker, it is a peptide that is indicative of cardiac fibrosis and inflammatory status and may be useful for evaluating cardiac and renal function in HF patients. We observed no decrease in galectin-3 levels after ARNI treatment. Our patients were relatively stable with no HF admission within at least the previous 6 months. Therefore, baseline galectin-3 levels (10.3±5.6 ng/mL) in our patients were below the normal upper limit of 17.7 ng/mL and appeared to be lower than those previously reported by McCullough et al.³³ In addition, the levels of ST2, a marker of myocardial fibrosis, all-cause death, and cardiovascular death, were unchanged in the ARNI group.²¹ ST2 levels were not higher in the ARNI group than previously proposed thresholds (35 or 28 ng/mL).³⁴ Normal values for galectin-3 and ST2 may partly explain the lack of changes observed after the treatment program in the ARNI group.

Clinical Implications

The current Japanese guidelines published at the end of 2021 recommended switching from ACEi to ARNI for HF patients with LVEF <40%. The present study, which enrolled HF patients with LVEF <50%, was approved and registered with the Japanese Registry of Clinical Trials in December 2021. The results obtained suggest that prescribing ARNI to stable outpatients with relatively low BNP levels may not only reduce LV end-diastolic and end-systolic volumes but also further attenuate LV fibrosis. These favorable effects are expected to prevent a further decline in LV diastolic function and the future exacerbation of HF.

Study Limitations

This study has several limitations. First, the sample size was small, and we enrolled HF patients with LVEF <50%. In HFrEF patients (LVEF <40%) in the ARNI group (n=19), no significant changes were observed in ECV or LVEF (P=0.659 and 0.647, respectively). Second, patients with a history of HF hospitalization within the previous 6 months were excluded, and all patients had been on uptitrated HF medications for at least 4 weeks. Therefore, early HF pharmacotherapy may have already induced reverse LV remodeling, resulting in no improvement in LVEF after ARNI treatment. In addition, the lack of continuous data regarding the time since the initial HF diagnosis limits our ability to evaluate whether patients with a shorter history of HF diagnosis exhibit more pronounced ECV reductions. Third, 50% of patients did not reach the maximum ARNI dose (400 mg), and medication dosages adhered to Japanese guidelines, which are generally lower than those in the US and Europe. Fourth, the relatively low baseline levels of ST2 compared with previously proposed thresholds may have contributed to the difficulty in detecting significant changes following ARNI treatment. Fifth, the use of sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists was limited. Finally, the small sample size limits the statistical power, particularly in subgroup analyses of ischemic and non-ischemic HF.

Conclusions

Nine months of treatment with ARNI significantly reduced LV volume and mass, and these changes were accompanied by decreases in both ECM and ICM, which consequently did not affect LVEF or ECV in HF patients with LVEF <50%. These results suggest that ARNI improved LV tissue characteristics and protected against further LV remodeling in HF patients with LVEF <50%, even those with a stable and mild symptomatic status.

Sources of Funding

This study did not receive any specific funding.

Disclosures

K.D. has received lecture fees from Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Company Limited, Nippon Boehringer Ingelheim Co., Ltd., Novartis Japan, and Takeda Pharmaceutical Company Limited, as well as departmental research grant support from Daiichi Sankyo Company Limited, Shionogi Co., Ltd., Takeda Pharmaceutical Company Limited, Abbott Japan LLC, Otsuka Pharmaceutical Co., Ltd., Novartis Japan, Novartis Japan, Kowa Company, Ltd., Dainippon Sumitomo Pharma Co., Ltd., and Ono Pharmaceutical Co., Ltd. The other authors have no financial conflicts of interest to declare.

IRB Information

This study was approved by thee Ethics Committee of Mie University Hospital (No. CRB4180006).

Data Availability

The deidentified participant data will not be shared.

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