A Study on the Effects of Short-term Sacubitril/Valsartan Treatment on Left Ventricular Functions Using 2D and 3D Echocardiography in Female Patients with Heart Failure with Reduced Ejection Fraction

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INTRODUCTION

Heart failure (HF) is a condition where functional or structural abnormalities of the heart impair blood filling or ejection, leading to systemic symptoms.^[1] HF with reduced ejection fraction (HFrEF) is outlined as ejection fraction (EF) <40% along with symptoms of failure. Pathological remodeling makes a major contribution to the course of HF.^[1] It is regulated by various neurohormonal pathways such as renin–angiotensin–aldosterone system (RAAS), sympathetic system, and natriuretic peptide pathway. The suppression of RAAS along with preservation of natriuretic peptide from lysis is the cornerstone of therapy in HF. Angiotensin receptor-neprilysin inhibitor (ARNI) is a combination drug of Sacubitril/Valsartan (S/V) that block angiotensin II receptors and at the same time inhibits Neprilysin, an enzyme which degrades natriuretic peptides resulting in vasodilation, reduction of myocardial hypertrophy, fibrosis and causes diuresis, which has shown clinical benefits in HF patients especially in reduced EF. In various clinical trials, ARNI had shown effective reduction mortality in HF patients in comparison to traditional treatment.^[2]

For decades, two-dimensional echocardiographic (2D ECHO) has been used regularly for assessing left ventricular function by measuring EF. However, 2D left ventricular ejection fraction (LVEF) is dependent on operator expertise, good imaging plane, requires manual tracking of endocardium at the end of diastole and end of systole, and is thus a much more time-consuming procedure. Poor image quality has the ability to obscure the accuracy of 2D LVEF. Other disadvantages of 2D LVEF include poor replicability and its lack of precision in spotting minor functional shifts.^[3] Recent progress in 3D echocardiography has made it much easier and more accurate to study the left ventricle. This technique provides multiple options for LV volumetric and functional analysis. Apical foreshortening is avoided, with volume derived from direct geometric assumptions, unlike 2D.^[4]

Utilizing global longitudinal strain (GLS) serves as an advanced imaging modality for evaluating left ventricular systolic function, offering enhanced sensitivity in detecting subtle myocardial contraction abnormalities that may precede overt manifestations of cardiac disease.^[5] The advantages of 3D GLS include superior reproducibility and heightened sensitivity to minor myocardial functional changes. It has lesser operator dependency in comparison to LVEF. Similar to its 2D counterpart, 3D GLS is more reliable and can precisely predict mortality better than 3D LVEF.^[6] Till date, a small number of literatures are available evaluating S/V effects on cardiac functions using 3D echocardiography and 3D GLS.

MATERIALS AND METHODS

This is a single-center, open-label, non-randomized study carried out at a tertiary center of southern Odisha named MKCG Medical College and Hospital. Patients consulting the cardiology department of this hospital from September 1^st, 2024, to October 31^st, 2024 (2 months) with HFrEF (LVEF <40%), fulfilling the inclusion and exclusion criteria were included.

The sample size was calculated based on an expected mean improvement in 3D GLS of 1.5% following 6 weeks of SV therapy, with a standard deviation of 2.5%, α = 0.05, and 80% power. Using a paired t-test formula, the minimum required sample size was estimated to be 22. To account for possible dropouts or incomplete follow-up (10–20%), a final target enrollment of 27 patients was planned. Finally, 34 consecutive, consenting female patients, after fulfilling inclusion and exclusion criteria, were taken up for this study.

The ethical clearance for the study was obtained from the Institutional Review Board of MKCG MCH, Berhampur. The study’s purpose and procedures were clearly explained, and written informed consent was obtained from all participants and their attendants in their preferred language. Patient information remained strictly confidential and was never disclosed at any time.

While including patients for this study, patients aged between 18 and 80 years presenting as HFrEF (2D LVEF <40%) who were already receiving Guideline-directed medical therapy (GDMT) (except ARNI) were considered. Those Patients with worsening HF requiring inotropic support, poor echo window, and having contraindications to SV treatment were excluded from the study.

After obtaining informed consent, each participant underwent a thorough clinical evaluation, including medical history, physical examination, and routine blood tests. All the patients were receiving GDMT during inclusion, comprising of Beta blocker, SGLT2 inhibitor, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (ACEi/ARB), and mineralocorticoid receptor antagonists. ARNI is only the new addition in place of ACEi/ARBs, with a washout period of 36 h for ACEi. During the study, patients maintained the doses of all GDMTs except ARNI to rule out the effect of cardiac remodelling of these drugs.

Echocardiography was done with GE Vivid E95 machine by a Single Operator according to the American Society of Echocardiography guidelines.^[7] 5S and 4V transducers were used for Data acquisition and measurements. Simpson’s biplane method was used for 2D LVEF assessment. Two-dimensional GLS was assessed using automated function imaging, with end-systolic manual tracing of the endocardial border in apical four-, three-, and two-chamber views. For three-dimensional (3D) measurements, the system created border tracings automatically, with manual corrections made if needed. The final Global strain parameter for the whole left ventricle (LV) was visualized on a bull’s-eye map. After follow-up, these patients were again evaluated using the same 2D and 3D parameters after 6-week short-course treatment of SV in guideline-approved doses. Representative echocardiographic images demonstrating the methodology of strain and ejection fraction assessment are shown in Figure 1.

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Figure 1:

(a) Echocardiographic (ECHO) image showing 3D global longitudinal strain measurement. (b) ECHO image showing 2D global longitudinal strain measurement. (c) ECHO image showing 3D left ventricular ejection fraction measurement. (Source: Current study)

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RESULTS

A total of 34 patients were enrolled in the study during a 2-week timeframe. All the patients were monitored over the next 6 weeks, with dose adjustments made every 2 weeks. Table 1 presents the clinical and demographic details of the enrolled participants.

AS depicted in Table-1 and Figure-2, Majority of subjects were aged beyond 50 years, with a mean age of presentation being 56.2 years, with a standard deviation of 10.3 years in the overall study groups. The NIHD group had a higher mean age of presentation, which is 58.5 years with a standard deviation of 8.8 years, in comparison to the IHD group with a mean age of 53.5 years with a standard deviation of 11.4 years. This shows a widely varied presentation age range of IHD.

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Figure 2:

Baseline characteristics of study subjects. (BMI: Body mass index, IHD: Ischemic heart disease. Source: Present study)

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The Body Mass Index of study subjects was identical in both groups. Most patients in our study were overweight with an overall Body mass index (BMI) of 29.5 kg/m² with a standard deviation of 6.7 kg/m². BMI was 30 and 29 kg/m² in NIHD and IHD groups, respectively.

About 67% (67.6 %) of study subjects were suffering from diabetes, which was equally distributed in NIHD and IHD patients, comprising 66.7% and 68.7%, respectively.

About 61% (61.7%) of study subjects were hypertensives, and when compared in NIHD and IHD patients, it was found to be 61.1% and 62.5%, respectively.

The functional class of patients was compared between groups. About 58% (58.8%) were presented in NYHA Class II, along with 35.3% and 5.9% subjects in NYHA Class III and NYHA Class IV, respectively as shown in Table 1 and Figure 3.

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Figure 3:

New York Heart Association (NHYA) class of study subjects. (IHD: Ischemic heart disease. Source: Present study)

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Echocardiography of all enrolled patients was done at the baseline and 6 weeks of ARNI treatment. All 2D and 3D echocardiographic features are described in Table 2.

As presented in Figure 4, the mean 2D LVEF at baseline was 29.9%. After 6 weeks of ARNI treatment, a statistically significant (P < 0.05) increase in EF to 33.1% observed. In a subgroup analysis, both groups showed an increase in LVEF, but the increase was not statistically significant in the IHD group (P = 0.07).

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Figure 4:

Change in 2D left ventricular ejection fraction during 6 week follow up. (IHD: Ischemic heart disease. Source: Present study)

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In comparison to 2D, 3D Echo showed better results in both groups. The mean 3D ejection fraction (LVEF) at baseline was 29.2%. After 6 weeks of ARNI treatment, this value increased to 33.9%, and it was statistically significant with P < 0.05. In subgroup analysis, both groups showed an increase in LVEF, and contrary to 2D Echo findings, the increase was statistically significant in both groups (P < 0.05) as summarized in Figure 5.The mean 2D GLS at baseline was −9.5%. After 6 weeks of ARNI treatment, this value increased to −11.6% (P < 0.05). In subgroup analysis, both groups showed an improvement in 2D GLS, which was −10–−12.9% and −8.9–−9.6% in NIHD and IHD groups, respectively, and both were statistically significant (P < 0.05) as shown in Figure 6.

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Figure 5:

Change in 3D left ventricular ejection fraction during 6 week follow up. (IHD: Ischemic heart disease. Source: Present study)

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Figure 6:

Change in 2D global longitudinal strain during 6 week follow up. (IHD: Ischemic heart disease. Source: Present study)

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The mean 3D GLS at baseline was −9.3%. Following 6 weeks of ARNI treatment, this value improved to −11.3% (P < 0.05). In subgroup analysis, both the NIHD and IHD groups showed a significant improvement in 3D GLS, from −9.8% to −11.3% in the NIHD group and from −8.7% to −9.5% in the IHD group (both P < 0.05). This is well summarized in Figure 7.

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Figure 7:

Change in 3D global longitudinal strain during 6 week follow up.

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DISCUSSION

S/V appears to reshape the trajectory of HFrEF by helping restore balance to the body’s disrupted neurohormonal systems as suggested by emerging researches.^[2] SV’s influence on heart structure changes has previously been validated through conventional two-dimensional transthoracic echocardiographic evaluation (TTE). However, limited evidence is available to show the impact of S/V using speckle tracking analysis, especially in Indian populations. Our study’s main innovation is the detailed evaluation of key echocardiographic changes after optimizing S/V therapy in ischemic and non-ischemic HFrEF cases, using 2D and 3D echocardiography to assess important heart function markers.

Mantegazza et al.^[8] conducted a study involving fifty-one patients and concluded that S/V induced significant changes in both 2D and 3D parameters in NIHD patients as well as the overall patient group. In IHD patients, statistically significant changes were observed only in 3D EF measurements. They also examined other parameters such as right ventricular function, left atrial volume index, and natriuretic peptide levels, all of which showed significant improvement.

Almufleh et al.^[9] performed a study on 48 HFrEF cases who were treated with SV for 3 months. SV was found to improve EF, but the rate of response was invariable between cases with ischemic cardiomyopathy and non-ischemic cardiomyopathy (P = 0.550).

Öz et al. did a similar study in 100 patients of HFrEF evaluating effects of 3-month S/V therapy and found significant improvement of LV systolic functions in both ischemic and non-ischemic HFrEF patients.^[10]

In the current study, 34 patients were examined, with 16 classified as having IHD and 18 as non-ischemic (NIHD). The groups were nearly equal in size and showed no significant differences at baseline in terms of risk factors and 2D and 3D echocardiographic parameters.

At the 6-week follow-up, there was a notable increase in 2D and 3D LV longitudinal strain as well as LVEF in the overall population, primarily led by the non-ischemic (NIHD) group. In the IHD group, a smaller yet significant improvement in LVEF was observed, but this was only detectable with 3D EF (P < 0.05) and GLS parameters (P < 0.05), not with 2D EF (P = 0.07). Post-myocardial infarction, the left ventricle can undergo substantial 3D morphological transformations that often escape detection through traditional 2D echocardiographic imaging. Although a marked change in left ventricular function by using 2D Echo after mid-term and long-term follow-ups after starting S/V in HF cases was reported in a previous study by Mantegazza et al.,^[8] one old study found no differences in improvement between IHD and NIHD cases.^[9] Therapies involving ARNI and ACEi can enhance the structural configuration of the left ventricle and support better diastolic performance in HF patients, with ARNI demonstrating superior improvements over ACEi in a recent study by Taufiqurrahman in Indonesia.^[11]

As noted in this study, EF enhancement in IHD cases might be less (0.7% mean by 2D), this is statistically significant with the use of 3DEF and it is well supported by improvement in GLS, which suggests that SV is also a valuable therapeutic option for ischemic patients with HFrEF for optimal medical therapy.

CONCLUSION

In HFrEF patients, S/V treatment demonstrated beneficial effects on LVEF and strain parameters. However, the impact on left ventricular (LV) systolic function varied significantly between ischemic and non-ischemic etiologies, with non-ischemic patients showing the most substantial improvements. Accurate evaluation of cardiac reverse remodeling in HFrEF is crucial for determining prognosis and establishing a personalized therapeutic approach. In this regard, 3D transthoracic echocardiography (TTE) offers added value over routine 2D TTE by providing a more comprehensive assessment of LV function and detecting minute changes in left ventricle size and function that may be missed by 2D imaging. Short-term treatment with S/V can lead to early enhancements in left ventricle functions, and GLS serves as an effective tool for identifying these changes and monitoring initial therapeutic impact.