Does Speckle Tracking Transthoracic Echocardiography Indicate Subtle Changes in Left Ventricular Function in Heart Failure Patients with Reduced Ejection Fraction Treated by Sacubitril-valsartan?

Abstract

Background:

In heart failure patients and reduced ejection fraction (HFrEF), assessing subtle changes in left ventricle (LV) function is crucial for monitoring treatment efficacy. This study aims to determine the effect of valsartan/sacubitril on LV ejection fraction (EF) assessed by two-dimensional (2D) transthoracic echocardiography (TTE) in comparison to that assessed by 2D TTE speckle tracking in patients with HFrEF ≤35% after 6 months of treatment.

Patients and Methods:

A prospective study will be conducted on 200 heart failure patients with reduced EF (HFrEF) undergoing sacubitril-valsartan treatment. Each participant underwent a comprehensive evaluation, including physical examination, history taking, serial 12-lead electrocardiogram, and 2D echo to evaluate cardiac parameters. In addition, 2D speckle tracking echocardiography (STE) assessments were conducted before and after 6 months of valsartan/sacubitril treatment.

Results:

The enrolled patients had an average age of 48 years with 63% females. At the beginning of the study, 9 (4.5%) patients were classified as New York Heart Association (NYHA) FC I, 120 (60%) as NYHA FC II, 64 (32%) as NYHA FC III, and 7 (3.5%) as FC IV. Following treatment, 82 (41%) patients improved to NYHA FC I, and 118 (59%) were in NYHA FC II. Notably, 82 (41%) patients showed improved left ventricular EF (LVEF), detected either by traditional TTE or STE, whereas 118 (59%) showed no improvement in EF through traditional TTE. In addition, 74 (37%) patients demonstrated improvement detected by STE. In contrast, 44 (22%) patients demonstrated no improvement in EF detected by either TTE or STE.

Conclusion:

STE was a more reliable diagnostic method for seeing early LVEF improvement in patients with HFrEF receiving valsartan/sacubitril treatment not seen by conventional TTE.

INTRODUCTION

The renin–angiotensin–aldosterone system (RAAS) can be activated due to a maladaptive response in the pathophysiology of heart failure. RAAS activation has detrimental side effects on the progression of the illness, including vasoconstriction, hypertension, higher hormone aldosterone levels, elevated sympathetic tone, and, ultimately, and cardiac remodeling. Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) substantially reduce morbidity and mortality as a result of heart failure by inhibiting these maladaptive components.[1,2] High brain natriuretic peptide (BNP) and N-terminal-pro BNP levels characterize heart failure exacerbations because the natriuretic peptide system is simultaneously activated. This compensatory process decreases blood pressure (BP), sympathetic tone, and aldosterone levels while causing vasodilation, natriuresis, and diuresis. The natriuretic peptide system affects the development of heart failure favorably and operates in opposition to the RAAS. Their beneficial effects are prolonged by inhibiting the neprilysin (NEP) enzyme’s activity, which breaks down natriuretic peptides. NEP is an enzyme that breaks down natriuretic peptides.[3] The combination medication valsartan/sacubitril, previously called LCZ696, comprises the NEP inhibitor sacubitril and the angiotensin II (Ang-II) receptor blocker valsartan. NEP is necessary to break down Ang-II, so if NEP is inhibited, Ang-II will build up instead. NEP inhibitors cannot effectively counteract the excess Ang-II on their own; they must always be paired with an ARB.[4] Sacubitril should not be combined with ACEI due to the elevated risk of angioedema if ACEI and angiotensin receptor neprilysin inhibitor (ARNI) are paired or in proximity. Bradykinin is another significant component broken down by NEP. Likewise, NEP inhibition will induce a buildup of bradykinin. To reduce the risk of angioedema after moving from ACEI to valsartan/sacubitril, a 36-h washout period is recommended.[5] Acute and chronic heart failure should be diagnosed and treated by the 2020 ESC Guidelines. The drug is suggested as a replacement for ACE-I in ambulatory patients with HFrEF who continue to be symptomatic after receiving the best possible care from an ACE-I, a beta-blocker (BB), and a mineralocorticoid receptor antagonist (MRA). This will lower the risk of HF hospitalization and death.[6] Evaluation of the left ventricle (LV) systolic function represents the basis of the echocardiographic assessment. Left ventricular ejection fraction (LVEF) is the most widely used measurement. The combined effects of radial thickening, circumferential and longitudinal contraction, and apical and basal rotation lead it to occur. However, LVEF has several disadvantages connected with the idea and imaging techniques.[7] The left ventricle (LV) base and apex rotate in inverse directions alongside its longitudinal axis during systole due to the distinctive double-helical structure of myocardial fibers, and the algebraic subtraction of this rotation leads to an LV twist. The muscle activity causes the LV to shorten longitudinally as the base travels toward the apex. As a result, myocardial torsion, a crucial aspect of cardiac function, causes the LV to twist and shorten simultaneously, causing systolic ventricular contraction.[8] Because of its excellent spatial and temporal resolution, as well as its reliable reproducibility among different observers, independence from the insonation angle, and inability to be influenced by the translational movements of the heart, speckle tracking echocardiography (STE) stands as a valuable tool of echocardiographic to estimate the myocardial function. In addition, it is used to evaluate the torsion mechanics involving twist and untwist. The torsion mechanics have become cutting-edge, trustworthy quantitative parameters for evaluating LV function. Beyond the traditional indices of LV function, twist and rotational factors may give effective full information.[9] In the current study, we aim to estimate the impact of valsartan/sacubitril on the left ventricle’s myocardial mechanics in heart failure patients and reduced ejection fraction (HFrEF). Besides, the study aims to retrospectively explore the effect of sacubitril/valsartan treatment and the outcome on LVEF using TTE and two-dimensional (2D) STE.

PATIENTS AND METHODS

Study period and setting

This prospective study was conducted at Minia University Hospital in Egypt from March 2022 to March 2023, following approval from the hospital ethics committee and obtaining written consent from each participant.

Participant enrollment and characteristics

A total of 200 patients diagnosed with heart failure with reduced ejection fraction (HFrEF) were included in the trial. Inclusion criteria comprised LVEF below 40%, New York Heart Association class III or IV symptoms, and systolic blood pressure (SBP) exceeding 105 mmHg. Demographic information and thorough medical history were collected from participants.

Baseline assessment

Baseline vital signs, 2D parameters (left ventricular end-diastolic volume [LVEDV], left ventricular end-systolic volume [LVESV], LVEF, and E/e), and speckle tracking parameters (global longitudinal strain [GLS] A4 and GLS A2) were recorded at the beginning of the study. All patients were on stable doses of guideline-directed medical therapy, including ACE inhibitors, BBs, and MRAs.

Exclusion criteria

Exclusion criteria were applied to pregnant or breastfeeding women, those with hypersensitivity to study drugs, inotropic drug use, history of angioedema, previous heart transplant, recent cardiac resynchronization therapy (CRT) or CRT-Defibrillator implantation, recent hospital discharge for heart failure, history of bile acid sequestering substance use, hepatic patients, refusal of informed consent, and prior treatment with sacubitril-valsartan. Patients with serum potassium >5.2 mEq/L at screening and recent intravenous diuretic therapy were also excluded from the study.

Treatment protocol

Patients in the study were indeed on optimized therapy at baseline, and sacubitril/valsartan was the only drug added during the observation period. All eligible patients were assigned to valsartan/sacubitril. Those on ACE inhibitors underwent a 36-h washout before starting valsartan/sacubitril at an initial dose of 24/26 mg twice daily, with titration over 2–4 weeks to the maximum tolerated dose. Participants underwent a thorough evaluation, including a full medical history review, 12-lead electrocardiogram, traditional transthoracic echocardiography (TTE), and 2D speckle-tracking echocardiography. A Vivid E9 ultrasound equipment was used for the standard echo-Doppler study, adhering to the American Society of Echocardiography standards. LV parameters, mitral valve velocities, and other relevant measurements were obtained. Apical second-harmonic B-mode and short-axis images were collected for speckle tracking. LV endocardial borders were manually marked, and automated speckle tracking was performed. Twist and untwist characteristics were analyzed using basal and apical short-axis datasets.

Statistical analysis

Data analysis was conducted using SPSS software (IBM SPSS version 29.0.2). Descriptive statistics were used for numerical data, and qualitative comparisons were made using the Chi-square test. The Paired sample t-test was applied to compare means within a single group. A significance level of P < 0.05 was considered.

RESULTS

Demographic and clinical characteristics

The mean age of the participants was 48.2 years, comprising 74 males (37%) and 126 females (63%). Mean BP values were 115.1 mmHg (SBP) and 75.8 mmHg (diastolic blood pressure), with a mean pulse rate of 80.6 beats/min and RR of 15 cycles/min. The average body mass index was 26.6 kg/m². Our study tracked the distribution of patients across heart failure classes at the study’s commencement and 6 months later. In Class 2, 60% of patients persisted in this category after 6 months, compared to the initial 59%. Class 3 initially had 32% representation (64 patients), but none remained in this class after 6 months. Similarly, none of the patients in Class 4 (initially 3.5%) retained this classification after 6 months. Remarkably, Class 1, initially consisting of 4.5% (nine patients), saw a substantial increase to 41% after 6 months Table 1.

Table 1.

Demographic and clinical characteristics

Variable	Mean/frequency (%)
Age (years)
Mean (SD)	48.2 (9.27)
Range	31–68
Gender
Male	74 (37)
Female	126 (63)
BMI (kg/m2)
Mean (SD)	26.6 (2.8)
Range	18–36
SBP
Mean (SD)	115.2 (5.1)
Range	100–130
DBP
Mean (SD)	75.85 (4.8)
Range	65–88
Heart rate (beat/min)
Mean (SD)	80.6 (10.1)
Range	56–99
Respiratory rate (breath/min)
Mean (SD)	15.1 (2.1)
Range	12–24
NYHA functional class before treatment
Class 1	9 (4.5)
Class 2	120 (60)
Class 3	64 (32)
Class 4	7 (3.5)
NYHA functional class after treatment
Class 1	82 (41)
Class 2	118 (59)

SD=Standard deviation, BMI=Body mass index, NYHA=New York Heart Association, SBP=Systolic blood pressure, DBP=Diastolic blood pressure

Effect of valsartan/sacubitril on cardiac parameters

We indicated a 41% improvement in both LVEF and ejection fraction (EF), whereas 37% exhibited enhanced GLS without concurrent improvement in EF. Approximately 22% of patients did not show improvement in either EF or GLS. These findings underscore the nuanced effects of valsartan/sacubitril on distinct cardiac parameters in heart failure patients Table 2.

Table 2.

Valsartan/sacubitril effect on ejection fraction and global longitudinal strain

Variable	Frequency (%)
Improved EF by TTE and GLS by 2D STE	82 (41)
Improved GLS by 2D STE, not improved EF by TTE	74 (37)
Neither improved EF by TTE nor GLS by 2D STE	44 (22)

GLS=Global longitudinal strain, EF=Ejection fraction, STE=Speckle tracking echocardiography, TTE=Transthoracic echocardiography, 2D=Two-dimensional

We also found that EF before and after treatment was statistically significant (P < 0.001). We also found significant differences in GLS A4 and GLS A2 before and after treatment (P < 0.001 for each). Although we discovered a significant difference in LVESV and E/è before and after treatment (P < 0.001 for each), no significant difference was observed in LVEDV due to the treatment (P = 0.83). In our study, the patients’ distribution over heart failure classes at the study onset and after 6 months of follow-up was assessed. In Class 1, there were nine patients (4.5%) at the beginning, significantly increasing to 82 patients (41%) after 6 months. In Class 2, most patients (60%) remained in this category, with minimal change after 6 months (59%). Notably, in class 3, there were 64 patients (32%) at the beginning, but after 6 months, none of the patients remained in this class. Similarly, in class 4, there were seven patients (3.5%) initially, and none of them remained in this class after 6 months, signifying an improvement in their heart failure status (P < 0.001), The P values indicate statistical significance, with classes 1, 3, and 4 showing significant changes over the 6 months Table 3.

Table 3.

Valsartan/sacubitril effect on left ventricular ejection fraction and global longitudinal strain (n=200)

Variable	Before treatment	After treatment	P
EF
Mean (SD)	34.86 (2.6)	35.65 (2.63)	<0.001
Range	28–39.6	29–40
GLS
Mean (SD)	−15.3 (−2.4)	−18.4 (−2.3)	<0.001
E/è
Mean (SD)	11.2 (2.7)	9.14 (2.34)	<0.001
Range	2–17	2–15
LVEDV
Mean (SD)	139.3 (7.3)	139.2 (10.5)	0.83
Range	123–155	34–158
LVESV
Mean (SD)	89.7 (4.7)	89 (4.44)	<0.001
Range	80–98	77–98
NYHA class
Class 1	9 (4.5)	82 (41)	<0.001
Class 2	120 (60)	118 (59)
Class 3	64 (32)	0
Class 4	7 (3.5)	0

LVEDV=Left ventricular end-diastolic volume, GLS=Global longitudinal strain, SD=Standard deviation, NYHA=New York Heart Association, EF=Ejection fraction, LVESV=Left ventricular end systolic volume

Regarding the patients with improved EF by TTE and GLS by STE, no significant increases in EF were observed before and after treatment (P < 0.001) Table 4. In addition, we found significant increases in GLS A4 and GLS A2 before and after treatment (P < 0.00 for each). As regards the patients who showed an improvement in GLS by STE and no improvement in EF by TTE, we reported significant increases in GLS A4 and GLS A2 before and after treatment (P < 0.001 for each). Furthermore, no significant difference was observed in EF due to the treatment (P = 0.15) Table 5.

Table 4.

Patients with improved ejection fraction and global longitudinal strain (n=82)

Variable	Before treatment (EF1)	After treatment (EF2)	P
EF
Mean (SD)	34.55 (2.42)	36.4 (2.27)	<0.001
Range	28–38	30–40
GLS
Mean (SD)	−14.75 (2.1)	−19.36 (1.76)	<0.001

EF=Ejection fraction, SD=Standard deviation, GLS=Global longitudinal strain

Table 5.

Patients with improved global longitudinal strain, not ejection fraction (n=74)

Variable	Before treatment	After treatment	P
EF
Mean (SD)	35.25 (2.76)	35.3 (2.8)	0.15
Range	29–39.6	29–39
GLS
Mean (SD)	−15.1 (2.6)	−18.4 (2.5)	<0.001

EF=Ejection fraction, SD=Standard deviation, GLS=Global longitudinal strain

DISCUSSION

The combination of valsartan/sacubitril acts as a NEP inhibitor and ARB. This grouping has demonstrated a 20% drop in cardiovascular-related mortality and hospitalization due to heart failure compared to enalapril in the PARADIGM-HF trial across various age groups.[10,11,12,13,14] This treatment effectively rebalances the renin–angiotensin–aldosterone and natriuretic peptide systems.[15,16] According to the latest Heart Failure Guidelines, valsartan/sacubitril is suggested as a Class I substitute for ACEI for HF ambulatory patients with HFrEF who still suffer from symptoms despite optimal care, including ACEI (or an ARB if ACEI is intolerable), a BB, and MRA.[16] Despite these recommendations and broadening indications, its incorporation into clinical practice has not met anticipated levels.[17] Various experimental and retrospective trials showed that valsartan/sacubitril promotes primary reverse remodeling in HFrEF patients, associated with a considerable improvement in LVEF and reduction in LV. These effects were observed with nonischemic and ischemic HFrEF patients. In addition, studies confirmed a remarkable enhancement in systolic pulmonary artery pressure, diastolic function, and mitral and tricuspid valve insufficiency.[18,19] The diabetic effect on valsartan/sacubitril therapy outcome associated with LV reverse remodeling was studied in patients with HFrEF. Valsartan/sacubitril is not linked to decreased ventricular tachyarrhythmia as a risk in patients with chronic HFrEF.[20] 2D-STE is an innovative tool to evaluate the LA and LV mechanical function. Analyzing LA myocardial deformation through longitudinal strain analysis provides a more sensitive insight into LA phasic function than volumetric measurements.[21] Strain analysis enables the assessment of the cardiac cycle in three phases: the reservoir phase during systole with LA filling, the conduit period in early diastole with passive LV filling, and the contractile phase with dynamic contractility in late diastole.[22] The regional LV’s longitudinal, radial, and circumferential mechanics can be precisely examined with 2D STE. During the examination, the 2D STE showed a subclinical strain impairment in the longitudinal, radial, and circumferential directions in patients with cardiovascular-related risk factors.[23] Furthermore, GLS represents a sensitive and precise marker for assessing cardiac remodeling and function. GLS finds extensive clinical use in evaluating conditions such as ischemic heart disease, cardiomyopathies, diastolic dysfunction, and subclinical myocardial dysfunction in patients with valve diseases or individuals undergoing chemotherapy.[24] However, no prospective evidence of valsartan/sacubitril therapy effects was reported using STE on LA phasic strain and LV deformation parameters. More investigation is needed to understand better the reverse remodeling mechanism associated with valsartan/sacubitril to support implementing this treatment as a prognostic indicator in clinical procedures.[25,26] This study examines the LVEF improvement resulting from sacubitril/valsartan treatment, utilizing TTE and 2D STE. While TTE lacks sensitivity in detecting these changes, 2D STE is anticipated to provide a more sensitive response. According to our study’s changes in cardiac parameters over 6 months, the LVEDV and LVESV were declined, whereas the LVEF was increased. Finally, the E/è ratio decreased. This aligns with the findings of Elshafey et al.,[9] who showed significant improvement in congestion and dyspnea symptoms after 6 months of follow-up in patients treated with ARNI. This improvement was coupled with enhanced diastolic indices, possibly due to chronic LV unloading and reduced LV end-diastolic pressure, indicated by the decrease in tricuspid flow velocity. Trials over laboratory animals indicated that valsartan/sacubitril showed a significant increase in LVEF and a trend toward enhanced reverse modeling compared to valsartan alone.[27] Extensive data strongly support the impact of valsartan/sacubitril on LVEF and reverse myocardial remodeling, aligning with findings from the PROVE-heart failure trial. In this trial, researchers noted improved cardiac function and structure within 6 months. By 1 year, additional enhancements in LVEF and volumes occurred, with one-quarter of the population showing an absolute LVEF increase exceeding 13%. This trial relied on alterations in LV end-systolic, diastolic, and left atrial (LA) volumes to draw these conclusions.[28] In a study conducted by Mazzetti et al.,[29] It has been demonstrated that ARNI therapy significantly affects ventricular volumes in heart failure patients. More specifically, ventricular volumes were significantly decreased over time as a result of ARNI therapy. Ventricular volumes were found to be significantly decreased after 6 months as compared to baseline in research assessing the effects of sacubitril/valsartan on patients with heart failure. Positive left ventricular remodeling, which is a good result for heart failure patients, is indicated by this reduction in ventricular volumes. Furthermore, conventional TTE has shown improvements in heart sizes and EF linked to ARNI therapy. The overall beneficial effects of ARNI therapy on cardiac shape and function are facilitated by these improvements in ventricular sizes and function. The findings underscore the significance of valsartan/sacubitril in promoting LV reverse remodeling, supported by tissue-tracking analyses revealing enhanced LV systolic deformation velocity and diastolic strain rate indices in the longitudinal direction. These improvements in myocardial deformation indices suggest a potential contribution to the positive outcomes observed in the larger-scale PARADIGM-HF trial.[30]

Strength and limitations

This study presents valuable insights into the effects of valsartan/sacubitril treatment on heart failure patients with reduced EF (HFrEF). It contributes to the understanding of nuanced improvements in NYHA functional classes, EF, and GLS. Utilizing both traditional TTE and 2D STE adds depth to the assessment, revealing more sensitive responses. The study addresses a critical gap in the prospective evidence for valsartan/sacubitril therapy’s impact on LA phasic strain and LV deformation parameters, enhancing the knowledge base in this domain. Despite its strengths, the study has limitations. The sample size may restrict the generalizability of findings, especially when exploring correlations between etiology and treatment response. The absence of a control group or comparison with standard heart failure treatments limits the ability to attribute observed changes solely to valsartan/sacubitril. In addition, the retrospective exploration of sacubitril/valsartan treatment outcomes on LVEF using TTE and 2D STE lacks a direct comparison with a control group. Future studies with larger, diverse samples and controlled designs can address these limitations, providing a more comprehensive understanding of treatment outcomes.

CONCLUSION

This study investigated the effects of valsartan/sacubitril treatment on heart failure patients with HFrEF. After 6 months of treatment, significant changes were observed in the distribution of patients across the assigned primary NYHA functional classes. Notably, Class 3 and Class 4 patients showed significant improvement, with none remaining in these classes after treatment. Furthermore, the study analyzed the impact of treatment on EF and GLS. The results indicated a substantial increase in EF and GLS after treatment, signifying the positive effect of valsartan/sacubitril in improving cardiac function. In addition, the study highlighted the specific improvements in GLS among patients, even when EF did not significantly change.

Author contributions

Every author contributed to the development and design of the study. All authors actively participated in clinical research, including material preparation, data collection, and analysis. All authors collectively wrote the initial draft of the manuscript, and they provided feedback on earlier versions.

Ethical statement

The study was approved by the institutional Ethics Committee of Minia University Hospital in Egypt (Approval No:20-2022).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.