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Study protocol. CRT = cardiac resynchronization therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MV = mitral valve; S/V = sacubitril/valsartan; TTE = transthoracic echocardiography.
Source publication
In terms of sacubitril/valsartan (S/V)-induced changes in heart failure with reduced ejection fraction (HFrEF) via three-dimensional (3D) transthoracic echocardiography (TTE) and S/V effects based on HF aetiology, data are lacking. We prospectively enrolled 51 HFrEF patients (24 ischaemic, 27 non-ischaemic). At baseline and at 6-month follow-up (6M...
Contexts in source publication
Context 1
... criteria included (i) poor endocardial visualisation; (ii) intolerance or adverse effects to S/V treatment requiring its interruption; and (iii) a necessity of cardiac resynchronization therapy (CRT) during the study observation. To assess the LV diastolic function by 2D parameters, patients were also excluded in the case of arrhythmias during the echocardiographic examination or if they had undergone previous mitral valve repair or replacement (Figure 1). At baseline, each patient underwent blood tests for N-terminal pro-B type natriuretic peptide (NT-proBNP) dosage, clinical evaluation, and a TTE study the day before interrupting ACEi or ARB. ...
Context 2
... our final population included 51 patients (47% IHD and 53% non-IHD). The diastolic function was assessable in a subset of patients (n = 40), since its evaluation was not feasible in nine cases due to atrial fibrillation, in one case for previous MitraClip implantation, and in one patient due to previous prosthetic mitral valve implantation ( Figure 1). ...
Citations
... Continuing forward, Sacharczuk et al. guide us through the intricate landscape of HF treatment. Here, the HF specialist emerges as the linchpin, translating personalized approaches into effective interventions, ensuring a seamless integration of therapies aimed at improving cardiac function, as also demonstrated in both small and larger trial (3)(4)(5)(6). ...
... Moreover, our experience confirmed how these results were paralleled by a significant reverse LV remodelling with a decrease in both 2D and 3D LV volumes and by an improvement in diastolic dysfunction and filling pressures. 36 The effects were consistent regardless of aetiology, even if more pronounced in non-ischaemic HFrEF patients. ...
In the last decades, the pharmacological treatment of heart failure (HF) become more complex due to the availability of new highly effective drugs. Although the cardiovascular effects of HF therapies have been extensively described, less known are their effects on cardiopulmonary function considered as a whole, both at rest and in response to exercise. This is a ‘holistic’ approach to disease treatment that can be accurately evaluated by a cardiopulmonary exercise test. The aim of this paper is to assess the main differences in the effects of different drugs [angiotensin-converting enzyme (ACE)-inhibitors, Angiotensin II receptor blockers, β-blockers, Angiotensin receptor-neprilysin inhibitors, renal sodium-glucose co-transporter 2 inhibitors, iron supplementation] on cardiopulmonary function in patients with HF, both at rest and during exercise, and to understand how these differences can be taken into account when choosing the most appropriate treatment protocol for each individual patient leading to a precision medicine approach.
... Our results confirm the favorable effect of sacubitril/valsartan on circulating HFrEF biomarkers, a surrogate of clinical and prognostic benefits observed in multiple clinical trials conducted with ARNI during the last years [9][10][11][12]. Interestingly, while both NT-proBNP and sST2 progressively decreased as the drug dose increased, the overtime kinetics of these changes is significantly different. ...
N-terminal pro-B-type natriuretic peptide (NT-proBNP) and soluble interleukin 1 receptor-like 1 ST2 (sST2) are biomarkers used to grade heart failure with reduced ejection fraction (HFrEF) severity. Both are potential targets of HFrEF treatment, but the first is associated with the patient’s hemodynamic status, while the second is more indicative of the inflammatory status and of myocardial fibrosis. The aim of this study was to assess the kinetics of these biomarkers after treatment with sacubitril/valsartan in HFrEF.
We analyzed blood samples of patients with HFrEF at baseline (before sacubitril/valsartan treatment), after 1, 2, and 3 months (respectively, after a month taking the 24/26 – 49/51 – 97/103 mg twice daily, or b.i.d., doses), and 6 months after the maximum-tolerated dose was reached (end study).
We obtained samples from 72 patients with HFrEF (age 64.0 ± 10.5 years, 83% males). NT-proBNP and sST2 values progressively and significantly reduced to 37% and 16%, respectively, with a greater reduction for NT-proBNP (p < 0.001). Specifically, NT-proBNP reduced from 1144 [593–2586] pg/mL to 743 [358–1524] pg/mL and sST2 from 27.3 [20.5–35.0] ng/mL to 23.1 [15.9–30.7] ng/mL, p for trend < 0.001 in both cases. The reduction of the two biomarkers over time occurred with statistically significant different kinetics: deferred for sST2 and faster for NT-proBNP. No significant changes in renal function and potassium levels were recorded.
These findings suggest that, in patients with HF, sacubitril/valsartan effects on the cardiovascular system share a double pathway: a first, hemodynamic, faster pathway and a second, non-hemodynamic anti-fibrotic, delayed one. Both likely contribute to the sacubitril/valsartan benefits in HFrEF.
... The CPET changes were paralleled by a decrease of LV volumes (both EDV and ESV), LA volumes, PAPs and MR, as previously published by our group [35,36]. Interestingly, we showed that 32 patients (33%) improved LVEF from < 40 to more than 40%, meeting the criteria for HF with improved EF (HFimpEF). ...
Purpose
Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses.
Methods
We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose.
Results
Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610–2757] to 780 [372–1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42–7.71] to 2.35% [1.24–4.96], p = 0.003.
Conclusions
A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.
... Among those, Sacubitril/Valsartan combines an angiotensin receptor blocker with a neprilysin inhibitor (angiotensin receptor-neprilysin inhibitors, ARNIs). In spite of its favorable effects on cardiac remodeling, functional capacity, and natriuretic peptides, its mechanisms of action are unclear [2,3]. Indeed, it has 2 of 14 been suggested both hemodynamic and non-hemodynamic mechanisms may contribute to these effects. ...
Sacubitril/Valsartan, used for the treatment of heart failure (HF), is a combination of two drugs, an angiotensin receptor inhibitor, and a neprilysin inhibitor, which activates vasoactive peptides. Even though its beneficial effects on cardiac functions have been demonstrated, the mechanisms underpinning these effects remain poorly understood. To achieve more mechanistic insights, we analyzed the profiles of circulating miRNAs in plasma from patients with stable HF with reduced ejection function (HFrEF) and treated with Sacubitril/Valsartan for six months. miRNAs are short (22–24 nt) non-coding RNAs, which are not only emerging as sensitive and stable biomarkers for various diseases but also participate in the regulation of several biological processes. We found that in patients with high levels of miRNAs, specifically miR-29b-3p, miR-221-3p, and miR-503-5p, Sacubitril/Valsartan significantly reduced their levels at follow-up. We also found a significant negative correlation of miR-29b-3p, miR-221-3p, and miR-503-5p with VO2 at peak exercise, whose levels decrease with HF severity. Furthermore, from a functional point of view, miR-29b-3p, miR-221-3p, and miR-503-5p all target Phosphoinositide-3-Kinase Regulatory Subunit 1, which encodes regulatory subunit 1 of phosphoinositide-3-kinase. Our findings support that an additional mechanism through which Sacubitril/Valsartan exerts its functions is the modulation of miRNAs with potentially relevant roles in HFrEF pathophysiology.
... In addition, sacubitril/valsartan can obviously increase cGMP levels in circulation, inhibit the expression of gene programs related to cardiac fibroblasts, reduce the activation and proliferation of fibroblasts, improve the degree of myocardial stiffness, and delay cardiac hypertrophy and remodeling (36,37). Our studies showed that LAD, LVPWT, IVSd, LVDd, LVEDV, and LVESV were significantly decreased after the treatment of sacubitril/valsartan, which suggested that sacubitril/valsartan could reverse left ventricular remodeling to some extent, which is consistent with previous trials among patients with HFrEF (38)(39)(40)(41). However, our study showed no significant difference in structural changes in the right ventricular after the treatment of sacubitril/valsartan among the MHD patient with HFpEF, which might suggest that structural changes in the right ventricular require a longer treatment period. ...
Introduction:
Heart failure with preserved ejection fraction (HFpEF), which is a common co-morbidity in patients with maintenance hemodialysis (MHD), results in substantial mortality and morbidity. However, there are still no effective therapeutic drugs available for HFpEF currently. Sacubitril/valsartan has been shown to significantly improve clinical outcomes and reverse myocardial remodeling among patients with heart failure with reduced ejection fraction (HFrEF). The effect of sacubitril/valsartan in MHD patients with HFpEF remains unclear. Our study was designed to assess the efficacy and safety of sacubitril/valsartan in MHD patients with HFpEF.
Methods:
A total of 247 MHD patients with HFpEF treated with sacubitril/valsartan were included in this retrospective study. Patients were followed up regularly after medication treatment. The alterations in clinical, biochemical, and echocardiographic parameters before and after taking sacubitril/valsartan were collected. In addition, the safety of the sacubitril/valsartan treatment was also assessed. Among those 247 patients with MHD, 211 patients were already in treatment with angiotensin converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) before being treated with sacubitril/valsartan. We also performed an analysis to compare the differences between the 211 patients who had previously received ACEi/ARB treatment and the 36 patients who were sacubitril/valsartan naive.
Results:
Among those 247 patients with MHD, compared with baseline levels, systolic blood pressure (BP) (149.7 ± 23.6 vs. 137.2 ± 21.0 mmHg, P < 0.001), diastolic BP (90.2 ± 16.1 vs. 84.5 ± 14.1 mmHg, P < 0.001), heart rate (83.5 ± 12.5 vs. 80.0 ± 8.7 bpm, P < 0.001), N-terminal B-type natriuretic peptide precursor (NT-proBNP) [29125.0 (11474.5, 68532.0) vs. 12561.3 (4035.0, 37575.0) pg/ml, P < 0.001], and cardiac troponin I [0.044 (0.025, 0.078) vs. 0.0370 (0.020, 0.064) μg/L, P = 0.009] were markedly decreased after treatment with sacubitril/valsartan. New York Heart Association (NYHA) functional class showed a notable trend of improvement after 3-12 months of follow-up. Echocardiographic parameters including left ventricular posterior wall thickness (LVPWT) (11.8 ± 2.0 vs. 10.8 ± 1.9 mm, P < 0.001), intraventricular septal thickness in diastole (11.8 ± 2.0 vs. 11.2 ± 2.0 mm, P < 0.001), left ventricular end-diastolic diameter (53.8 ± 6.9 vs. 51.2 ± 7.1 mm, P < 0.001), left atrial diameter (LAD) (40.5 ± 6.2 vs. 37.2 ± 7.2 mm, P < 0.001), left ventricular end-diastolic volume (LVEDV) [143.0 (111.5, 174.0) vs. 130.0 (105.0, 163.0) ml, P < 0.001], left ventricular end-systolic volume (LVESV) [57.0 (43.0, 82.5) vs. 48.0 (38.0, 74.0) ml, P < 0.001], and pulmonary arterial systolic pressure [39.0 (30.5, 50.0) vs. 28.0 (21.0, 37.5) mmHg, P < 0.001] were significantly reduced after initiating the treatment of sacubitril/valsartan. The parameters of left ventricular diastolic function including E/A ratio [0.8 (0.7, 1.3) vs. 0.9 (0.8, 1.3), P = 0.008], maximal tricuspid regurgitation velocity [2.7 (2.5, 3.2) vs. 2.4 (2.0, 2.8) m/s, P < 0.001], septal e'wave velocity (8.0 ± 0.6 vs. 8.2 ± 0.5 cm/s, P = 0.001), lateral e' wave velocity (9.9 ± 0.8 vs. 10.2 ± 0.7 cm/s, P < 0.001), E/e' [8.3 (6.4, 11.8) vs. 7.2 (6.1, 8.9), P < 0.001], and left atrial volume index (37.9 ± 4.2 vs. 36.4 ± 4.1 ml/m2, P < 0.001) were significantly improved by sacubitril/valsartan. Among 211 patients who were already in treatment with ACEi/ARB and 36 patients who were sacubitril/valsartan naive, the improvement of cardiac function demonstrated by clinical outcomes and echocardiographic parameters were similar to the previous one of the 247 MHD patients with HFpEF. During the follow-up, none of the patients showed severe adverse drug reactions.
Conclusion:
Our study suggested that sacubitril/valsartan treatment in MHD patients with HFpEF was effective and safe.
... Among those, Sacubitril/Valsartan has become part of now-a-days HFrEF common treatment strategy. Although its favorable effects on cardiac remodeling, functional capacity and natriuretic peptides have been already demonstrated (2,3), little is known about the mechanisms underlying these effects. Both hemodynamic and non-hemodynamic actions have been suggested, but at present poorly studied. ...
Purpose
Little is known about the mechanism underlying Sacubitril/Valsartan effects in patients with heart failure (HFrEF). Aim of the study is to assess hemodynamic vs. non-hemodynamic Sacubitril/Valsartan effects by analyzing several biological and functional parameters.
Methods
Seventy-nine patients (86% males, age 66 ± 10 years) were enrolled. At baseline and 6 months after reaching the maximum Sacubitril/Valsartan tolerated dose, we assessed biomarkers, transthoracic echocardiography, polysomnography, spirometry, and carbon monoxide diffusing capacity of the lung (DLCO).
Results
Mean follow-up was 8.7 ± 1.4 months with 83% of patients reaching Sacubitril/Valsartan maximum dose (97/103 mg b.i.d). Significant improvements were observed in cardiac performance and biomarkers: left ventricular ejection fraction increased (31 ± 5 vs. 37 ± 9 %; p < 0.001), end-diastolic and end-systolic volumes decreased; NT-proBNP decreased (1,196 [IQR 648–2891] vs. 958 [IQR 424-1,663] pg/ml; p < 0.001) in parallel with interleukin ST-2 (28.4 [IQR 19.4–36.6] vs. 20.4 [IQR 15.1–29.2] ng/ml; p < 0.001) and circulating surfactant binding proteins (proSP-B: 58.43 [IQR 40.42–84.23] vs. 50.36 [IQR 37.16–69.54] AU; p = 0.014 and SP-D: 102.17 [IQR 62.85–175.34] vs. 77.64 [IQR 53.55-144.70] AU; p < 0.001). Forced expiratory volume in 1 second and forced vital capacity improved. DLCO increased in the patients' subgroup ( n = 39) with impaired baseline values (from 65.3 ± 10.8 to 70.3 ± 15.9 %predicted; p = 0.013). We also observed a significant reduction in central sleep apneas (CSA).
Conclusion
Sacubitril/Valsartan effects share a double pathway: hemodynamic and systemic. The first is evidenced by NT-proBNP, proSP-B, lung mechanics, and CSA improvement. The latter is confirmed by an amelioration of DLCO, ST-2, SP-D as well as by reverse remodeling echocardiographic parameters.
Background
Heart failure (HF) significantly affects the morbidity, mortality, and quality of life of patients. New therapeutic strategies aim to improve the functional capacity and quality of life of patients while controlling HF-related risks. Real-world data on both the functional and cardiopulmonary exercise capacities of patients with HF with reduced ejection fraction upon sacubitril/valsartan use are lacking.
Methods
A multicenter, retrospective, cohort study, called REAL.IT, was performed based on the data collected from the electronic medical records of nine specialized HF centers in Italy. Cardiopulmonary exercise testing was performed at baseline and after 12 months of sacubitril/valsartan therapy, monitoring carbon dioxide production (VCO2) and oxygen consumption (VO2).
Results
The functional capacities of 170 patients were evaluated. The most common comorbidities were hypertension and diabetes (i.e., 53.5 and 32.4%, respectively). At follow-up, both the VO2 peak (from 15.1 ± 3.7 ml/kg/min at baseline to 17.6 ± 4.7 ml/kg/min at follow-up, p < 0.0001) and the predicted % VO2 peak (from 55.5 ± 14.1 to 65.5 ± 16.9, p < 0.0001) significantly increased from baseline. The VO2 at the anaerobic threshold (AT-VO2) increased from 11.5 ± 2.6 to 12.5 ± 3.3 ml/kg/min (p = 0.021), and the rate ratio between the oxygen uptake and the change in work (ΔVO2/Δwork slope) improved from 9.1 ± 1.5 to 9.9 ± 1.6 ml/min/W (p < 0.0001).
Conclusions
Sacubitril/valsartan improves the cardiopulmonary capacity of patients with HFrEF in daily clinical practice in Italy.
Recently established heart failure therapies, including sodium glucose co‐transporter 2 inhibitors, angiotensin‐neprilysin inhibitors, and cardiac resynchronization therapy, have led to both clinical and structural improvements. Reverse remodelling describes the structural and functional responses to therapy and has been shown to correlate with patients' clinical response, acting as a biomarker for treatment success. The introduction of these new therapeutic agents in addition to advances in non‐invasive cardiac imaging has led to an expansion in the evaluation and the validation of cardiac reverse remodelling. Methods including volumetric changes as well as strain and myocardial work have all been shown to be non‐invasive end‐points of reverse remodelling, correlating with clinical outcomes. Our review summarizes the current available evidence on reverse remodelling in heart failure by the non‐invasive cardiac imaging techniques, in particular transthoracic echocardiography.
The amount of evidence for guideline‐directed new heart failure (HFrEF) disease‐modifying drugs in the context of chronic kidney disease (CKD) is relatively modest, especially in end‐stage CKD. We report a case of dramatic reverse remodelling and disease regression in a naïve HFrEF young woman on haemodialysis treated with sacubitril/valsartan and SGLT2i. At 10‐month follow‐up, the patient normalized left ventricle and atrial volumes and improved ejection fraction to the normal range, assessed both by echocardiography and cardiac magnetic resonance. Cardiac biomarkers and exercise performance improved consensually. The haemodialysis protocol and the loop diuretic dose were unchanged within the whole period.
