Journal of Cardiovascular Translational Research

https://doi.org/10.1007/s12265-020-10041-4

ORIGINAL ARTICLE

Left-Ventricular Function After 3 Months

of Sacubitril-Valsartan in Acute Decompensated Heart Failure
Dino Mirić 1 & Darija Baković 1,2 & Davor Eterović 2,3 & Tomislav Sorić 4,5 & Vesna Čapkun 2,3 & Ivica Vuković 1,2 &
Darko Duplančić 1,2 & Ana Barac 6

Received: 2 April 2020 / Accepted: 26 May 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
There is limited data on the effect of sacubitril-valsartan on the echocardiographic parameters in acute decompensated heart
failure (ADHF). We prospectively enrolled 68 consecutive patients with ADHF who received sacubitril-valsartan (N = 34, S/V
group) or angiotensin inhibition-based therapy (N = 34, ACEi/ARB group). Two-dimensional echocardiography with speckle
tracking (2D-STE) was performed at baseline and after 3 months of treatment. Changes in 2D-STE parameters, including global
longitudinal strain (GLS), were compared between the groups by t test and ANCOVA. Baseline characteristics were similar
between the groups. Following 3 months of treatment, LVEF and GLS significantly improved in the S/V group (mean LVEF
from 27 to 34.5% and GLS from − 6.6 to − 9.4%) but not in ACEi/ARB group. The improvement in LVEF and GLS was more
prominent in patients with non-ischemic cardiomyopathy. In patients with ADHF 3-month treatment with sacubitril-valsartan,
compared to guideline directed medical therapy without sacubitril, improves LVEF and GLS.

Keywords Two-dimensional speckle tracking echocardiography . Global longitudinal strain . Acute decompensated heart
failure . Sacubitril/valsartan . Heart failure

Introduction by acute HF symptoms of new or worsening preexisting car-

diomyopathy, represent a particular challenge with reported 1-
Heart failure (HF) is a growing public health problem associ- year readmission and death rate of 32% and 31%, respectively
ated with significant morbidity and mortality estimated to af- [3].
fect more than 12% of the population over age 80 in devel- Angiotensin-converting-enzyme inhibitors (ACEis) and
oped countries in 2016 [1, 2]. Hospitalizations for acute de- angiotensin receptor blockers (ARBs) have become the cor-
compensated heart failure (ADHF), a condition characterized nerstone of medical therapy in patients with HF reduced ejec-
tion fraction (HFrEF), and their use is recommended in the
setting of ADHF as well as chronic stable HF [1]. The favor-
Dino Mirić and Darija Baković contributed equally to this work.
able effect of ACEi/ARBs on left ventricular (LV) function
Editor-in-Chief Enrique Lara-Pezzi oversaw the review of this article and LV dimensions has been well recognized in patients with
acute myocardial infarction [4, 5], as well as chronic HFrEF
* Ana Barac [6, 7].
[email protected] Sacubitril-valsartan is the novel combination angiotensin
1 receptor-neprilysin inhibitor (ARNI) which was recently ap-
Department of Cardiology, University Hospital Split, Split, Croatia
2
proved in the treatment of chronic HFrEF, based on the sig-
University of Split School of Medicine, Split, Croatia nificant improvement in CV outcomes, including reduction in
3
Department of Nuclear Medicine, University Hospital Split, all-cause mortality, hospitalization due to HF, and the risk of
Split, Croatia CV death, in comparison to enalapril [8, 9]. Among hospital-
4
Department of Urology, County Hospital Zadar, Zadar, Croatia ized patients with ADHF, early initiation of sacubitril-
5
University of Osijek Faculty of Medicine, Osijek, Croatia valsartan led to a significant reduction in NT-proBNP concen-
6
Cardio-Oncology Program, MedStar Heart and Vascular Institute, tration [10] indicating beneficial effects on neurohormonal
Georgetown University, Washington, DC, USA activation and hemodynamic stress.
 J. of Cardiovasc. Trans. Res.

Echocardiography plays an important part in establishing Study Procedures The sacubitril-valsartan therapy was initiat-
the diagnosis of HF, guiding management (e.g., device eligi- ed on in-patient basis after hemodynamic stabilization, with
bility) as well as HF risk and prognosis assessment. LV re- systolic blood pressure above 100 mmHg, no increase of in-
modeling and LV ejection fraction (LVEF), together with oth- travenous diuretics, vasodilators or inotropes in the last 6 h.
er echocardiographic parameters, have been shown to predict ACE inhibitors were withheld 2 days before initiation of
HF mortality and hospital readmissions [11]. Global longitu- sacubitril-valsartan. The sacubitril-valsartan starting dose
dinal strain (GLS) assessed by 2D speckle-tracking echocar- (24/26 mg twice daily) was increased to 49/51 and 97/
diography (2D-STE) is a relatively novel measure of myocar- 103 mg BID after 2 and 4 weeks, respectively, if there were
dial contractility which has been reported to predict adverse no side effects (symptomatic hypotension, hyperkalemia,
outcomes in patients with HFrEF [12]. Importantly, GLS was cough, dizziness, renal failure). The patients received other
superior to LVEF in predicting mortality and hospital guideline-directed medications for heart failure (diuretics,
readmissions in different HF cohorts [13] including ADHF beta-blockers, vasodilators) and medications to manage co-
[14]. morbidities (diabetes, hypertension, atrial fibrillation, hyper-
There is limited data on the effect of sacubitril-valsartan on thyroidism, ischemic heart disease, chronic obstructive pul-
parameters of LV function in patients with ADHF. We pro- monary disease) at the discretion of the treating physician.
spectively investigated changes in LV echocardiographic The patients in ACEi/ARB group were treated in the same
measures in HFrEF patients admitted with ADHF who were fashion for HF and comorbidities except for not receiving
treated with sacubitril-valsartan and compared them to pa- sacubitril-valsartan. After hemodynamic stabilization,
tients who received ACEi/ARB during 3 months post- guideline-directed therapy (including ACE inhibitors and
ADHF admission while continuing other guideline-directed ARBs) was continued with increases in the ACE/i/ARB doses
HF therapy. Our endpoints included changes in 2D-STE as tolerated.
GLS (primary outcome), LVEF, and LV remodeling. All patients underwent standard physical examination, 12-
lead ECG recording, transthoracic echocardiography includ-
ing end diastolic (EDV) and end systolic (ESV) LV volumes,
Methods LVEF, E/E′ ratio (presented as ratio of E wave velocity of the
diastolic mitral inflow and the E′ velocity of tissue Doppler),
Study Design and Patient Population We conducted a pro- left atrial volume (LAV), and GLS. These parameters were
spective, open-label, single-center trial that enrolled men and collected at baseline, after hemodynamic stabilization and pri-
women, 18 years of age and older, who were admitted to the or to initiating ACEi/ARB or sacubitril-valsartan treatment.
tertiary hospital for primary diagnosis of ADHF. Inclusion Following discharge, the patients continued on the allocated
criteria were previously known HF with proven LV dysfunc- HF therapy and presented for the follow-up study assessment
tion and LVEF of 40% or less and plasma N-terminal pro-B with transthoracic echocardiogram, 3 months after initiation
type natriuretic peptide (NT-proBNP) level ≥ 1600 pg/ml on of sacubitril-valsartan or allocation to the ACEi/ARB group.
current admission. Exclusion criteria were severe hypotension
with systolic blood pressure less than 100 mmHg, glomerular Echocardiography and 2D-STE GLS Analysis
filtration rate (eGFR) < 20 ml/min/1.73 m2, severe liver dys- Echocardiography examination was performed prospectively
function (as evidenced by total bilirubin > 3 mg/dl, AST/ALT using a commercially available system (Vivid 9, GE Medical
> 2× upper limit of normal, Child-Pugh B and C, biliary cir- System, Milwaukee, USA). All the data was stored digitally
rhosis), increased serum potassium level > 5.5 mmol/l, recent and analyzed on the Echo Pac workstation (GE Medical
acute coronary syndrome (within 3 months), active infection Systems, EchoPac PC, version 112). The examination was
or cancer, history of angioedema, pregnancy or breastfeeding, performed with the patients at rest using a left lateral decubital
hypersensitivity or intolerance to sacubitril-valsartan, ACE position. Blinded image analysis and echocardiographic mea-
inhibitors or ARBs, severe pulmonary hypertension and se- surements were performed by the same cardiologist, with ex-
vere valvular disease. pertise in 2D-STE who was blinded to any patient or clinical
Consecutive patients admitted to the University Hospital data. Simpson biplane method was used to calculate ESV,
Center Split in the period from November 2017 until EDV, LAV, and LVEF following the American Society for
February 2019 with primary diagnosis of ADHF were consid- E c h oc a r d i og r ap h y a n d E u r o p ea n A s s o ci a t i o n o f
ered for the study. The patients were assigned to sacubitril- Cardiovascular recommendations [15].
valsartan (S/V) or comparative (ACEi/ARB) group based on The 17-segment model of LV used to perform quantitative
the HF therapy that was initiated in the hospital, according to speckle tracking analysis is illustrated in Fig. 1. Images were
the treating physician preference. Patients in both groups were recorded from three projections, four chambers, two-chamber,
allowed to receive all other guideline-directed HF therapy and apical long axis with a frame rate of 50–60 fps. To obtain
including diuretics and beta-blockers. GLS, all strain values were averaged [15]. We considered
J. of Cardiovasc. Trans. Res.

Fig. 1 Left ventricular (LV) segmental longitudinal strain measured by each LV segment. Negative strain corresponds to fiber shortening and
2D-STE at baseline (a) and at 3-month follow-up (b) in acutely decom- positive strain to fiber lengthening. The LV myocardial regions with
pensated patient with heart failure treated with sacubitril-valsartan. The similar strain are displayed in a red to blue scale. ANT = anterior, ANT_
greater longitudinal myocardial fiber shortening (peak systolic strain), the SEPT anteroseptal, INF inferior, LAT lateral, POST posterior, SEPT
greater the strain, expressed as percent systolic change and averaged over septal

normal value of GLS − 19.7% based on previously reported 3 months–value at baseline) normalized to its standard devia-
values for GE Medical System [16]. tion (as a measure of the heterogeneity of the effect). The
association between the different measures of the LV function
Statistical Analysis The primary endpoint was a change in was quantified by linear correlation coefficient (R). Our anal-
GLS from baseline to post 3 months of treatment. The sec- ysis had GLS as pre-specified primary outcome, therefore
ondary endpoints were the changes in LVEF, LAV, EDV, analyses were not corrected for multiple comparisons. Since
ESV, and E/E′. the comparisons were planned in advance, with GLS as the
primary outcome, the borderline statistical significance (0.95)
Study Power A decline in strain of 1.5% was considered clin- was not corrected for multiple comparisons. We used the
ically significant [17]. The sample size was determined based MedCalc Statistical Software version 17.9.4 (MedCalc
on the desired 90% power to detect a statistically significant Software bvba, Ostend, Belgium; http://www.medcalc.org;
(at P = 0.05 type I error level) change in GLS of absolute 1.5% 2017).
from baseline to 3 months after treatment between sacubitril/
valsartan and ACE/ARB group, assuming the effect size of 1.
This required having at least 23 patients in each group. We Results
decided to slightly increase the sample sizes to account for
possible losses in follow-up. Of 83 consecutive patients admitted with ADHF who met
inclusion criteria, 41 were treated with sacubitril-valsartan
Effect Size For both groups (sacubitril-valsartan and compar- and 42 with ACEi/ARB. In the sacubitril-valsartan (S/V)
ative group), the effect of the therapy was defined as the dif- group, 34 (83%) patients agreed to participate, compared to
ference in the parameters of LV function (GLS, EF, EDV, 37 (88%) patients in ACEi/ARB group (Fig. 2). In 3 patients
ESV, LAV, and E/E ) between measurement at 3 months on ACEi/ARB therapy, the 2D-STE data were unavailable,
and at baseline. The mean values of these differences were resulting in final number of 34 patients in the ACEi/ARB
compared between the two groups, as well as between the group. Baseline demographic and clinical characteristics are
non-ischemic and ischemic patients in sacubitril-valsartan shown in Table 1. The patients were predominantly men (82%
and ACE/ARB group, by t test. In addition, ANCOVA was and 71% in S/V and ACEi/ARB group, respectively) with
used to control for the variables that could confound these similar distribution of ischemic and non-ischemic cardiomy-
comparisons (e.g., the baseline value of the parameter com- opathy among the groups. The baseline hemodynamic mea-
pared, or of the other parameter that apparently differed be- surements and echocardiographic parameters including
tween the groups compared). To rank the effects of the therapy LVEF, GLS, and LAV were not significantly different be-
on different LV parameters, the effect size was defined as the tween patients treated with sacubitril-valsartan and
mean difference of the parameter in question (value at ACEi/ARB.
 J. of Cardiovasc. Trans. Res.

Fig. 2 Flowchart of study

enrollment and participation

Individual patients’ paired values (baseline and at 3 months cardiomyopathy (29.9 to 34.5%) for LVEF and (− 6.8 to −
follow-up) of LVEF and GLS, are illustrated in Fig. 3. In 8.8%) for GLS. The use of ANCOVA produced negligible
patients who received sacubitril-valsartan therapy most of differences compared to t-test.
the LVEF and GLS data are seen above the line of identity
consistent with significant improvement in LVEF (mean in-
crease from 27 to 35%, P < 0.001) and in GLS (mean increase Discussion
from − 6.6 to − 9.4%, P < 0.001). In contrast, in ACEi/ARB
group, the values clustered around the identity line indicate In our prospective study of patients admitted with ADHF,
absence of significant change in LVEF (mean value 29.2% at treatment with sacubitril-valsartan for 3 months led to im-
baseline and 28% at follow-up, P = 0.64) or GLS (− 6.6% at provement in echocardiographic parameters including
baseline to − 6.68, P = 0.89). In S/V group, the response was LVEF, GLS, and diastolic function. In contrast, the control
greater in patients with non-ischemic compared to ischemic group of patients treated ACEi/ARB for 3 months after
cardiomyopathy. Table 2 shows details of changes in echocar- ADHF admission had no significant changes in cardiac
diographic parameters from baseline to after 3 months of treat- function.
ment. In S/V group LVEF increased on average by 7.5% Our study provides new data about the effects of sacubitril-
absolute LVEF points while there was no significant change valsartan on measures of LV function in HFrEF patients with
in LVEF in ACEi/ARB group. The increase in LVEF was acute decompensation which have been understudied in prior
primarily driven by a relatively larger decrease in ESV than reports. Recent observational studies in stable, chronic HFrEF
in EDV. Similarly, there was 42% relative improvement in have reported varying degrees of improvement in LVEF after
GLS in S/V group compared to 1% relative GLS improvement initiation of sacubitril-valsartan mostly without comparison
in ACEi/ARB group. In 23/34 (68%) of the patients in S/V group [18–20]. Almufleh et al. studied 48 patients with chron-
group, the absolute change in GLS was greater than 1.5% ic HFrEF and found a 5% increase in LVEF and improvement
which is considered clinically meaningful increase. The in- in measures of reverse remodeling 3 months after switching
creases in GLS correlated with increases in LVEF (R = 0.67; from ACE/ARB to sacubitril-valsartan. In a prospective ob-
P = 6 × 10−5). For both LVEF and GLS, the effect size was servational study of 230 HFrEF patients treated with
around 1. Patients treated with sacubitril-valsartan had im- sacubitril-valsartan for 10 months, LVEF increased by 3%
provement in the LV diastolic performance, as evidenced by compared to baseline. Parisi et al. reported a 5% improvement
the decreases in LAV and E/E (Table 2). in EF among 14 post-acute stabilized HF patients treated with
We then compared changes LV function within S/V and sacubitril/valsartan, without including the comparative group.
ACEi/ARB groups based on the etiology of cardiomyopathy. In our study of 68 patients with ADHF LVEF improved by 7.5
In patients with non-ischemic cardiomyopathy treated with absolute percentage points in patients treated with sacubitril-
sacubitril-valsartan, the increase in mean LVEF (23.8 to valsartan but showed not significant change in patients who
34.7%) and GLS (− 6.5 to − 10.2%) was higher compared to received ACEi/ARB therapy. These results agree with the
sacubitril-valsartan-treated patients with ischemic findings from the PIONEER-HF trial that showed reduction
J. of Cardiovasc. Trans. Res.

Table 1 Baseline characteristics

of acutely decompensated heart Demographic characteristics S/V ACE/ARB P*
failure patients with reduced N = 34 N = 34
ejection fraction treated with n (% N) or median (range) n (% N) or median (range)
sacubitril-valsartan (S/V) therapy
or angiotensin inhibition-based Age; median (range) 64 (32–90) 65 (32–90) 0.88
treatment (ACEi/ARB) Men 28 (82.4) 24 (70.6) 0.14
Non-ischemic cardiomyopathy 16 (47.0) 17 (50.0) 0.81
Diabetes mellitus 9 (26.5) 9 (26.5) 1.00
Hypertension 20 (58.8) 22 (64.7) 0.62
Hypercholesterolemia 10 (29.4) 12 (35.3) 0.60
Current smoker 7 (20.6) 7 (20.6) 1.00
Previous IM 17 (50.0) 11 (32.4) 0.22
Previous PCI 9 (26.5) 5 (14.7) 0.23
Previous CABG 5 (14.7) 7 (20.6) 0.52
Sinus rhythm 22 (64.7) 22 (64.7) 1.00
Atrial fibrillation 12 (35.3) 12 (35.3) 1.00
BMI (kg/m2) median (range) 26.5 (17–41) 26 (16–40) 0.80
Previous use of medications
ACE inhibitor or ARB 17 (50.0) 17 (50.0) 1.00
Beta-blocker 27 (79.4) 24 (70.6) 0.40
MRA 11 (32.4) 7 (20.6) 0.27
Loop diuretics 21 (61.8) 23 (67.6) 0.61
Nitrate 2 (5.9) 0 (0) 0.15
Digoxin 1 (2.9) 1 (2.9) 1.00
Clinical and echo parameters Mean ± SD Mean ± SD
Systolic BP (mmHg) 120.7 ± 19 126.5 ± 22.3 0.26
diastolic BP (mmHg) 76.8 ± 10.2 78.2 ± 11.7 0.59
heart rate (bpm) 91.3 ± 24.1 88.1 ± 24.1 0.60
LVEF (%) 27 ± 8.5 29.2 ± 9.9 0.33
EDV (ml) 180.2 ± 52.4 166.5 ± 47.2 0.26
ESV (ml) 132.6 ± 44.3 116.2 ± 38.6 0.11
GLS (%) − 6.6 ± 2.9 − 6.6 ± 2.4 0.98
LAV (ml) 104.8 ± 53.8 92.9 ± 37.1 0.30
E/E 16.6 ± 6.9 18.8 ± 6.9 0.23
NT-proBNP 6854 ± 4901 7091 ± 3453 0.91
Hemoglobin (g/L) 138.1 ± 15.6 135.4 ± 15.9 0.48
Creatinine (μmol/L) 108.3 ± 27.9 120.8 ± 80.3 0.39

Continuous variables with normal distribution were expressed as mean ± standard deviation (SD). If highly
skewed, continuous variables were presented as medians with ranges. Categorical variables were presented as %
LVEF left ventricular (LV) ejection fraction, EDV LV end-diastolic volume, ESV LV end-systolic volume, LAV
left atrial volume, E/E ratio between early mitral inflow velocity and mitral annular early diastolic velocity
*P values were calculated using t test for numerical variables and chi-square test for comparisons concerning
categorical variables

in NT-proBNP with sacubitril-valsartan [10, 13, 21] and sug- with decrease in ESV and borderline decrease in EDV, as well
gest that its early addition in acutely decompensated patients as with decreased LAV.
may improve outcomes by promoting reverse remodeling. The main novelty of our study is that sacubitril-valsartan,
The supporting data, showing an independent association be- but not ACE/ARB therapy, improved LV longitudinal strain
tween improvements in LV function and mortality of HFrEF in acutely decompensated HFrEF patients. The large, clinical-
patients, are provided by the large meta-analysis of Kramer ly relevant increase in GLS was seen in majority of patients on
et al. [21]. In our study, improvement in LVEF was associated sacubitril-valsartan, but not in ACE/ARB group. Several
 J. of Cardiovasc. Trans. Res.

Fig. 3 Changes in left ventricular ejection fraction (LVEF) and global patient-paired values of LVEF and GLS (baseline and follow-up) are
longitudinal strain (GLS) from baseline to after 3 months of therapy with shown for patients with non-ischemic (filled circles) and ischemic cardio-
sacubitril-valsartan or angiotensin inhibition (ACEi/ARB). Individual myopathy (empty circles)

previous studies have shown improvement in GLS in patients [24]. We hypothesize that discrepancies in the results may
with chronic stable HFrEF with addition of sacubitril- be in part due to different cohorts studied (acute vs chronic)
valsartan. In a retrospective cohort study by De Vecchis and distinct pathophysiology underlying acute decompensa-
et al., the use of sacubitril-valsartan during 14 months led to tion and chronic stable HF. While the EVALUATE-HF en-
improvement in GLS by 8% [22] and Abraham and Srinivas rolled stable outpatients with chronic HF, 81% of whom were
[23] observed improved GLS, but not LVEF, following receiving ARB/ACEi, our population consisted of patients
4 weeks of sacubitril-valsartan in 27 chronic HFrEF patients. hospitalized with acutely decompensated HF, only 50% of
In contrast to our findings, recently published EVALUATE- whom were previously treated with ARB/ACEi therapy. Our
HF (Effect of sacubitril-valsartan vs enalapril on aortic stiff- cohort is therefore more similar to the patients enrolled in
ness in patients with heart failure and reduced ejection fraction PIONEER-HF study [10], which demonstrated greater reduc-
a randomized clinical trial) showed no differences in measures tion in the NT-proBNP among hospitalized ADHF patients
of LV contractile function including LVEF and GLS between who received sacubitril-valsartan compared to enalapril-
HFrEF patients treated with sacubitril-valsartan or enalapril treated patients.
J. of Cardiovasc. Trans. Res.

LVEF left ventricular (LV) ejection fraction, EDV LV end-diastolic volume, ESV LV end-systolic volume, LAV left atrial volume, E/E′ ratio between early mitral inflow velocity and mitral annular early

The changes are expressed for each echocardiographic parameter as the value at 3 months–value at baseline (mean ± standard deviation, top row), and as the value at 3 months/value at baseline (geometric
0.051
GLS has been previously shown to predict mortality in

5 vs.

0.41
0.80
0.77
0.96

0.44
chronic HF patients independent of other echocardiographic

6
parameters [25]. In acute heart failure, the longitudinal strain

2 vs. 3

0.013
0.049
0.035
0.99

0.99
0.50
was also shown to have superior predictive value to LVEF,
where each 1% increase in longitudinal strain is associated

5 × 10−6
8 × 10−5

4 × 10−4
with a 5% decrease in mortality risk [26]. In our acutely
1 vs. 4

0.017
0.11

0.60
decompensated HFrEF patients, the improvements in GLS
P*

were seen in parallel and correlated with increases in LVEF.

− 2.82 ± 9.24 (0.94)

− 0.35 ± 1.58 (1.05)
− 1.47 ± 8.78 (0.95) Our study was focused on GLS and not powered for subgroup
1.70 ± 30.90 (1.01)

5.94 ± 18.63 (1.08)

6.94 ± 28.38 (1.05)
Ischemic6 (N = 17)

analyses, however we observed a trend in greater response to

sacubitril-valsartan therapy in non-ischemic compared to is-
chemic patients for LVEF, GLS, and LAV. While it may be
plausible to speculate that presence of myocardial scar may
Changes in echocardiographic parameters after 3 months of sacubitril-valsartan (S/V) or angiotensin inhibition-based treatment (ACE/ARB)

limit remodeling responses in ischemic myocardium, these

findings should be interpreted with caution. The adjusted
Non-ischemic5 (N = 17)

analysis of PARADIGM-HF trial, for example, did not dem-

− 0.76 ± 7.64 (0.98)
5.17 ± 36.82 (1.03)
6.35 ± 32.24 (1.06)
− 6.06 ± 15 (0.93)
0.19 ± 2.20 (0.97)

0.05 ± 7.60 (1.07)

Cardiomyopathy

onstrate differences in the effect of sacubitril-valsartan on

outcomes (composite outcome of cardiovascular death or
HF hospitalization and death from any cause) between pa-
tients with ischemic and non-ischemic etiology [27]. In our
study, baseline echocardiographic and laboratory parameters
were similar; however, patients with ischemic cardiomyopa-
Whole group4 (N = 34)

thy were older than those with non-ischemic cardiomyopa-

− 0.08 ± 1.91 (1.01)

− 1.57 ± 8.51 (0.99)

− 1.12 ± 8.12 (0.96)
3.44 ± 33.52 (1.02)
6.65 ± 29.91 (1.06)
0.12 ± 17.78 (0.99)
ACE/ARB group

thy. Due to the small sample size, we were not able to perform
statistical analyses according to the age group. Further inves-
tigations in larger cohorts are needed to understand possible
age-dependent effect of sacubitril-valsartan and replicate the
differences seen between patients with ischemic and non-
ischemic cardiomyopathy.
− 16.76 ± 29.10 (0.88)
− 9.71 ± 37.57 (0.95)

− 2.56 ± 24.40 (0.98)

− 1.97 ± 1.86 (1.30)

− 2.48 ± 4.18 (0.78)

The molecular mechanisms of sacubitril-valsartan in HF

Ischemic3 (N = 18)

4.56 ± 7.20 (1.15)

patients have not been completely understood. Its favorable

effects on LV stroke volume, longitudinal shortening, and EF
could be attributed in part to hemodynamic effects and reduc-
tion in cardiac preload [28]. Previous studies have suggested
that neprilysin inhibition may also play a more direct role in
Non-ischemic2 (N = 16)

cardiac remodeling by modulating direct myocardial effects

− 23.21 ± 21.93 (0.80)
− 30.36 ± 33.01 (0.75)
− 9.78 ± 24.62 (0.94)
− 3.65 ± 2.72 (1.56)

− 2.48 ± 3.76 (0.82)

of endogenous vasoactive peptides [29].

10.87 ± 9.47 (1.46)
Cardiomyopathy

Our study has several limitations. First, it is relatively

small, precluding multivariable analysis with appropriate ad-
justments. Second, as a single-center study and with predom-
inant male population, the extrapolation of its results to other
settings and women is limited. Third, the study was limited 3-
month follow-up. Finally, the levels of NT-proBNP were not
Whole group1 (N = 34)

− 19.68 ± 25.90 (0.84)

− 15.53 ± 31.55 (0.84)
− 9.74 ± 31.87 (0.94)

P values were calculated using t test

− 2.76 ± 2.42 (1.42)

− 2.48 ± 3.93 (0.80)

available during follow-up thus precluding the analysis of

7.53 ± 8.82 (1.28)

correlations between natriuretic peptides and LV remodeling

mean, brackets in bottom row)

which needs to be investigated in the future.

S/V group

In conclusion, in ADHF patients with reduced LVEF,

3 months of sacubitril-valsartan therapy resulted in significant
improvements in the GLS and LVEF which was not seen in
diastolic velocity

patients on angiotensin inhibition-based treatment.

Δ LVEF (%)
Δ EDV (%)

Δ LAV (%)
Δ GLS (%)

Δ ESV (%)
Table 2

Δ E/E

Clinical Relevance In patients with ADHF, 3-month treatment

with sacubitril-valsartan, compared to guideline directed
*
 J. of Cardiovasc. Trans. Res.

medical therapy without sacubitril, improves global longitudi- Swedberg, K., & Zile, M. R. (2014). PARADIGM-HF
Investigators and Comittees. Angiotensin-neprilysin inhibition ver-
nal strain and left ventricular ejection fraction.
sus enalapril in heart failure. The New England Journal of
Medicine, 371, 993–1004.
Compliance with Ethical Standards 9. Fala, L. (2015). Entresto (sacubitril/valsartan): First in class
angiotension receptor neprilysin inhibitor FDA approved for pa-
Conflict of Interest The authors declare that they have no conflict of tients with heart failure. American Health & Drug Benefits, 8(6),
interest. 330–334.
10. Velazquez, E. J., Morrow, D. A., DeVore, A. D., Duffy, C. I.,
Ethical Approval All procedures performed in studies involving human Ambrosy, A. P., McCague, K., Rocha, R., & Braunwald, E.
participants were in accordance with the ethical standards of the institu- (2019). Angiotensin-neprilysin inhibition in acute decompensated
tional and national research committee and with the 1964 Helsinki heart failure. The New England Journal of Medicine, 380(6), 539–
Declaration and its later amendments. Approval was granted by the 548.
Ethics Committee of University Hospital Centre Split, Croatia. 11. Thavendiranathan, P., Yingchoncharoen, T., Grant, A., Seicean, S.,
Landers, S. H., Gorodeski, E. Z., & Marwic, T. H. (2014).
Prediction of 30-day heart failure-specific readmission risk by echo-
Informed Consent Informed consent was obtained from all individual
cardiographic parameters. The American Journal of Cardiology,
participants included in the study.
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12. Saito, M., Negishi, K., Eskandari, M., Huynh, Q., Hawson, J.,
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