Results:
Our prospective study basically included 73 patients diagnosed as HFrEF based on conventional echocardiography study at the outpatient clinic of Menoufia university hospital, a total of 12 cases were excluded during the workflow of the follow ups either because of three cases missed connections, four cases developed severe renal impairment and CKD, three cases were uninterested to continue follow up, and four cases died of sudden cardiac death. Sixty-one patients succeeded to complete the time table of the study, 34 cases were treated by ARNI (ARNI group) and 27 cases were treated by traditional therapy (Traditional group), data reveled that at baseline there were no significant difference in between the traditionally treated and ARNI treated groups regarding basic characteristics, demographic data, symptoms, conventional and STE echocardiographic measurements. (Table.1)
After 6 months, both groups recalled doing the first follow up and there were remarkable differences in symptoms, conventional and STE echocardiography data (Table.2) there were very high statistically significant improvement in diastolic parameters either conventional E/A, E/e’, Tricuspid velocity or STE specifically untwist parameters (Untwist onset, and rate).while the ejection fraction and global LV longitudinal strain showed also improvement. For the final recall after 11 months, the data showed exponential improvement for both diastolic and systolic parameters with very high statistically significant improvement of untwist and twist parameters with remarkable improvement of ejection in the ARNI group versus the traditionally treated patients. (Table.3)
On another hand to show the pattern of temporal effect of ARNI therapy among the ARNI group itself we made comparisons between the ARNI group at different follow-ups and it also showed exponential improvement from baseline, 6 months and 11 months follow up with maximal improvement of untwist parameters, twist and ejection fraction after 11 months of follow up. (Table.4, 5)
As regard the ejection fraction of the ARNI group after 11 months it was positively correlated with LVGLS, Twist, Apical rotation, and negatively correlated with Untwist onset, and rate and basal rotation. (Table.6)(Figures1, 2, 3 and 4)
From all of these variables the only dependent variables for the improvement of EF% was the LVGLS, and Apical rotation. (Table.7)
As regard the prevalence of systemic hypertension in ARNI group it was (22cases from 34 ARNI treated patients (64%), we did comparison between baseline and 11 months follow up, data showed highly significant improvements in untwist and twist parameters, LVGLS% and EF% in comparison to the weaker however significant improvements in the normotensive group (12 cases).(Table.8,9)
Discussion:
The sound evaluation of cardiac function plays a crucial role in diagnosing cardiovascular diseases, initiating specific therapeutic interventions, monitoring treatment, and determining the prognosis of a variety of cardiovascular conditions. Echocardiography can provide valuable information about the anatomy and function of the heart. (15, 16) Left ventricular ejection fraction (LVEF) provides objective information about left ventricular (LV) systolic function. It has been used to diagnose and classify heart failure (HF),(17,18),determine the suitability of device therapy,(17,19) decide interventions for valvular heart diseases (VHDs),(20,21) determine the need for specific medications,(19) and predict prognosis.(22) However, LVEF is a volumetric parameter with ventricular load-dependence and had limitations such as significant inter- and intra-observer variability and geometric assumptions.(23) Moreover, LVEF does not represent intrinsic myocardial properties.
Strain is a dimensionless index of a change in length between 2 points before and after movement. Strain echocardiography was introduced to the clinical field about 20 years ago, making it a relatively new echocardiographic modality that can measure myocardial deformation. Unlike LVEF, myocardial strain, as calculated by strain echocardiography, can afford indices of regional and global myocardial systolic function noninvasively and objectively. (24)
Strain echocardiography has been used to diagnose subclinical disease states, (25, 26) monitor changes in myocardial function with specific therapies, (27) differentiate cardiomyopathies, (28) and predict the prognosis of several cardiovascular diseases independently of LVEF. (29, 30)
Although the physiological mechanisms of action of Sacubitril/Valsartan are well described, its effects on left ventricular remodeling and left ventricular ejection fraction (LVEF) have not been well studied. Left ventricular remodeling is a major mechanism underlying disease progression in patients with HFrEF (31). The degree of improvement in left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), LV dimensions, and LVEF with therapies are strongly correlated with clinical outcomes, including survival (32).
In the current study, we demonstrated that after 6 months of follow up on the ARNI treated group of patients the symptoms of congestion and dyspnea was remarkably improved this is accompanied with the improvement of diastolic indices that might be explained by a chronic state of LV deloading and reduction of LV end diastolic pressure indexed by the reduction of the tricuspid flow velocity, E/A , E/e’ also that could help in the initial improvement of LV global longitudinal strain which indicating that the maximized stretch of LV myocardium and wall tension are reduced with restoration of myocardial starling’s forces and this state prepare the LV myocardium recovering the global longitudinal strain. Beta-blockers, ACEi/ARBs, and MRAs have demonstrated potent effects on reverse remodeling and improvement in LVEF in multiple studies (33-36) Animal studies have shown that treatment with Sacubitril/Valsartan compared to Valsartan alone is associated with a statistically significant increase in LVEF and a trend towards improved reverse remodeling (37).
Heart failure has recently been classified according to alterations in the mechanical function of the LV (38). After having observed anomalous specific patterns of ventricular myocardial mechanics in different subsets of patients with heart failure, an alternative approach has been proposed for its characterization (38, 39). Accordingly, heart failure can be classified into three large subgroups: A) Predominant longitudinal dysfunction; B). Transmural dysfunction (longitudinal and circumferential); and C). Predominant circumferential dysfunction. This classification is based on the orientation of the myocardial fibers of the LV, which are arranged obliquely in a double helix shape. Endocardial fibers, which are aligned in a parallel fashion to the LV long axis, are mainly associated with longitudinal mechanics, while transmural fibers are mainly responsible for circumferential mechanics (40). The action of the latter is predominant due to its greater radius of action.
In the case of systolic dysfunction, twist serves as a compensatory mechanism, and the more its reduction the more advanced stage of the disease. In the dilated left ventricle, the fiber muscles in both layers are stretched and oriented more circumferentially, which leads to additional reduction in chamber contractility and torsion (41, 42). Thus, twist and torsion may be a sensitive marker of remodeling of LV wall architecture, useful in the monitoring of disease progression and response to therapy.
The last follow up of our patients groups after eleven months there were a lot of data that strongly supports the idea of the effect of Sacubitril/Valsartan of LV ejection fraction, and reverse myocardial remodeling which might go in agreement with the PROVE-HF trial (43), where the investigators stated that “although improvement in cardiac structure and function was present at six months, at 12 months, further improvement in LVEF and volumes was present, with 25 percent of the study participants experiencing an absolute LVEF increase of more than 13 percent”. In that trail they depend on changes in LV end systolic, diastolic and left atrial volumes, but in our study we choose a more precise STE deformational parameters, which had a more sensitive predictive values and accuracy, where we demonstrated that at eleven months most of the torsion mechanics and LV global longitudinal strain consequently LV ejection fraction in addition to the diastolic parameters as untwist rate and onset, that means systolic functional improvement and LV recovery.