Impact of sacubitril/valsartan on systolic heart failure: Right heart location and clustering analysis

Abstract

Background. Heart failure with reduced ejection fraction (HFrEF) is a heterogeneous syndrome. In heart failure (HF) classifications, right ventricle (RV) function was for a long time unrecognized in favor of left ventricular ejection fraction (LVEF). The response to sacubitril/valsartan might differ according to phenotypes and the impact of right ventricular characteristics on this response remains controversial.Objectives. First, we applied clustering analysis in a HFrEF population undergoing sacubitril/valsartan treatment according to guidelines, to identify phenotypes and their associated clinical outcomes. Secondly, we evaluated RV-remodeling. Materials and methods.It is a prospective, observational, single-center study conducted on 108 symptomatic patients (mean age 66 ±12.8 years, 22.2% women). First, the clustering analysis was applied in a HFrEF population undergoing sacubitril/valsartan treatment, according to the guidelines, in order to identify phenotypes and clinical outcomes associated with them. Secondly, we evaluated RV-remodeling.Results. Two distinct clusters were identified. Among the differences between phenotypes, RV (tricuspid annular plane systolic excursion (TAPSE) 16 ±4 mm compared to 19 ±4 mm, p < 0.001; RV free wall strain −19 ±5% compared to −21 ±4%, p = 0.046; RV fraction area change (FAC) 31 ±9% compared to 38 ±9%, p < 0.001), LV-filling pressure (E-wave deceleration time 138 (median: 41) ms compared to 180 (median: 94) ms, p < 0.001; E/e' 16.7 (median: 8.0) ms compared to 13.0 (median: 9.7) ms, p = 0.02) and creatinine level (106 ±34 µmol/L compared to 90 ±19 µmol/L, p = 0.002) were substantially different at the initiation of therapy. Major adverse cardiac events (MACEs) or death occurred in 38 out of 107 patients: 51. 1% in cluster 1 compared to 24.2% in cluster 2 (p = 0.0074). A significant improvement in RV-functional parameters was observed under treatment. The TAPSE improved and correlated with the change in left ventricular (LV) function. Yet, it did not correlate with systolic pulmonary artery pressure (sPAP) and LV end-diastolic diameter.Conclusions. The HFrEF phenotype characterized by more severe RV dysfunction has a worse prognosis during sacubitril/valsartan therapy. Both RV-and LV functions significantly improve when the patient is treated with sacubitril/valsartan.

Discovering Distinct Phenotypical Clusters in Heart Failure Across the Ejection Fraction Spectrum: a Systematic Review

“…We found 34 eligible clustering studies that were performed between 2012 and 2022, and used varying datatypes, clustering methods, and sample sizes (Table 1 ) [ 10 , 17 – 33 , 34 •, 35 – 38 , 39 •, 40 – 42 , 43 •, 44 – 49 ]. Clustering techniques that were used included hierarchical clustering ( n = 14) [ 10 , 22 , 24 , 25 , 27 , 28 , 31 , 34 •, 36 , 39 •, 40 , 45 , 47 , 49 ], LCA ( n = 10) [ 17 , 21 , 26 , 32 , 33 , 35 , 37 , 43 •, 46 , 48 ], PAM ( n = 5) [ 19 , 29 , 30 , 34 •, 38 ], k-means clustering ( n = 5) [ 23 , 34 •, 41 , 42 , 44 ], and model-based clustering ( n = 3) [ 18 , 20 , 34 •]. Dataset sizes ranged from 103 patients to 318,384 patients.…”

“…Dataset sizes ranged from 103 patients to 318,384 patients. Datatypes varied between registry-based data ( n = 6) [ 19 , 26 , 27 , 42 , 43 •, 46 ], cohort data ( n = 7) [ 20 , 22 , 24 , 28 , 30 , 38 , 41 ], EHR data ( n = 9) [ 10 , 23 , 29 , 31 , 34 •, 44 , 47 – 49 ], and trial data ( n = 12) [ 17 , 18 , 21 , 25 , 32 , 33 , 35 – 37 , 39 •, 40 , 45 ], using varying variable types for the clustering such as clinical variables ( n = 31), echocardiographic variables ( n = 7) [ 10 , 18 , 20 , 22 , 23 , 40 , 49 ], biomarkers ( n = 4) [ 24 , 28 , 38 , 41 ], hemodynamic parameters ( n = 1) [ 23 ], and demographic variables ( n = 1) [ 27 ]. The number of variables used for analysis also varied between 8 and 415, and the number of clusters discovered ranged between 2 to 15.…”

“…Still, most studies exceeded the threshold of 100 participants for each discovered subgroup ( n = 29). Description of missingness ranged from not mentioning missing values at all ( n = 11) [ 18 , 19 , 23 , 25 , 30 , 31 , 35 , 36 , 43 •, 44 , 48 ] to reporting percentage of missing for each variable ( n = 12) [ 10 , 20 – 22 , 24 , 26 , 29 , 37 , 39 •, 40 , 46 , 47 ], but also several studies have only given a very global description of the missingness in the dataset usually limited to which variables passed a specific threshold of missingness ( n = 11) [ 17 , 27 , 28 , 32 , 33 , 34 •, 38 , 41 , 42 , 45 , 49 ]. From the studies that describe handling of missingness they either performed complete case analysis ( n = 9) [ 26 , 32 , 33 , 36 – 38 , 39 •, 43 •, 46 ] or imputation ( n = 13) [ 10 , 17 , 18 , 20 , 22 , 24 , 29 , 34 •, 40 – 42 , 48 , 49 ].…”

Long-Term Effects of Sacubitril-Valsartan on Cardiac Remodeling: A Parallel Echocardiographic Study of Left and Right Heart Adaptive Response

“…LV function improvement obtained after S/V has a role in RV remodeling. The beneficial effects of S/V on biventricular structure and function may be partly explained by hemodynamic effects on peripheral resistance and natriuresis with a reduction of LV filling pressures and better LV-RV interactions [ 36 , 37 ]. However, the moderate correlation proved between right and ventricular function during follow-up in our analysis, lead us to consider several mechanisms linked to a beneficial effect of S/V on the RV side.…”

The history and mystery of sacubitril/valsartan: From clinical trial to the real world

“…A prospective single-center study of 108 patients with symptoms of HF shows that patients with HFrEF and severe right ventricular dysfunction have a worse prognosis than patients with mild right ventricular dysfunction after treatment with sacubitril/valsartan, although both groups show significant improvements in left and right ventricular function ( 81 ).…”