LCZ696 Therapy Research Articles

LCZ696 (sacubitril/valsartan) mitigates cyclophosphamide-induced premature ovarian failure in rats; the role of TLR4/NF-κB/NLRP3/Caspase-1 signaling pathway

AimCyclophosphamide (CP) is used to treat a variety of cancers and autoimmune illnesses. CP has been found to frequently cause premature ovarian failure (POF). The study's objective was to assess LCZ696's potential for protection against CP-induced POF in a rat model. Main methodsRats were randomly assigned into seven groups as follows: control, valsartan (VAL), LCZ696, CP, CP + VAL, CP + LCZ696, and CP + triptorelin (TRI). Ovarian malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), interleukin-18 (IL-18), IL-1β, and tumor necrosis factor-alpha (TNF-α) were assessed using ELISA. Serum anti-mullerian hormone (AMH), estrogen, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also measured using ELISA. The expression of NLRP3/Caspase-1/GSDMD C-NT and TLR4/MYD88/NF-B P65 proteins was estimated using western blot assay. The histopathology of the ovaries was also investigated. The estrous cycle, body, and ovarian weights were also monitored. Key findingsCP treatment significantly elevated levels of MDA, IL-18, IL-1β, TNF-α, FSH, LH, and up-regulated TLR4/NF-κB/NLRP3/Caspase-1 proteins, as compared to the control group, however, ovarian follicles count, and levels of GSH, SOD, AMH, and estrogen were reduced with CP administration. All the aforementioned biochemical and histological abnormalities were considerably alleviated by the LCZ696 therapy compared to valsartan alone. SignificanceLCZ696 effectively mitigated CP-induced POF, offering promising protection that could be related to its suppression power on NLRP3-induced pyroptosis and TLR4/NF-B P65 pathway.

Management strategies in heart failure with preserved ejection fraction.

The diagnosis and therapy of heart failure with preserved ejection fraction (HFpEF) remain challenging. Currently, there are ongoing discussions on whether the diagnosis of HFpEF should be based solely on left ventricular ejection fraction, which may not account for the heterogeneity of HFpEF syndrome. This aspect has been addressed by the recently proposed HFA-PEFF and the H2FPEF algorithms, which take numerous diagnostic modalities into account to establish the diagnosis of HFpEF. Moreover, this review focuses on the adequate treatment of comorbidities and risk factors in HFpEF that should be an essential part of any HFpEF therapy. Furthermore, the management of fluid level in HFpEF patients is pointed out, as it plays an important role in symptom control. In addition, the value of LCZ696 therapy in HFpEF is discussed. Although LCZ696 had neutral effects in the large PARAGON-HF trial, it had previously been granted an extended indication by the Food and Drug Administration. Since the publication of the EMPEROR-Preserved trial, empagliflozin now represents the first drug to significantly improve the prognosis of HFpEF patients. Therefore, the role of SGLT2 inhibitors in HFpEF management is highlighted. Overall, this review aims to enhance the knowledge on the diagnostic processes and best treatments available for HFpEF patients.

LCZ696 ameliorates lipopolysaccharide-induced endothelial injury.

Lipopolysaccharide (LPS)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases. LCZ696, the dual-acting angiotensin receptor blocker, and neprilysin inhibitor has been used for the treatment of heart failure with reduced ejection fraction. Recent work suggests that LCZ696 therapy might have an anti-inflammatory effect in cardiovascular tissue. In the current study, we show that LCZ696 attenuates LPS-induced oxidative stress by reducing the production of intracellular reactive oxygen species (ROS) and the measurements of malonyl dialdehyde (MDA) level in human umbilical vascular endothelial cells (HUVECs). LCZ696 inhibits LPS-induced expressions and secretions of the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-1α (IL-1α), and tumor necrosis factor β (TNF-β) as well as the chemokines, monocyte chemotactic protein 1 (MCP-1), and chemokine (C-X-C motif) ligand 1 protein (CXCL1). Additionally, we found that LCZ696 reduces LPS-induced expressions of vascular cell adhesion molecule 1 (VCAM-1) and P-selectin and the attachment of U937 monocytes to HUVECs. Mechanistically, LCZ696 prevents LPS-induced activation of the TLR4/Myd88 pathway and nuclear translocation of nuclear factor kappa-B (NF-κB) p65 factor. Based on these findings, we conclude that LCZ696 is capable of ameliorating LPS-induced endothelial dysfunction via anti-inflammatory properties.

Safety and Tolerability of Sacubitril/Valsartan Initiation in Inpatient Versus Outpatient Setting: A Retrospective Real World Study

The Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event (TRANSITION) and PIONEER-HF trialsa have shown that sacubitril/valsartan can be initiated early and safely in patients with heart failure with reduced ejection fraction (HFrEF) shortly after an acute heart failure episode during hospitalisation. However, it is unclear whether the results can be translated to Asian populations. Hence, this real-world study was designed with the aim of comparing the safety and tolerability of sacubitril/valsartan initiation in an inpatient versus outpatient setting. A retrospective review for all patients initiated with sacubitril/valsartan from 1 November 2015 to 30 September 2018 was conducted in a tertiary health care institution in Singapore. Patients with HFrEF and aged ≥21 years were included. Incidence of adverse drug reactions (ADRs) and discontinuation rate of sacubitril/valsartan were compared between initiation of sacubitril/valsartan in inpatient and outpatient settings. Reasons for discontinuation were investigated. Subgroup analysis was performed. Cox regression was used to analyse the primary outcomes. Of the 1,022 patients who were screened, 840 (289 inpatient group; 551 outpatient group) were included. The inpatient group experienced significantly higher ADRs (34.6% vs 22.7%; adjusted hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.68-3.10; p<0.01) and discontinuation rate (18.0% vs 10.3%; adjusted HR, 2.11; 95% CI, 1.37-3.26; p<0.01) than the outpatient group. The safety outcomes were consistent across all the subgroups. Initiation of sacubitril/valsartan in an inpatient group was associated with higher ADRs and discontinuation rate as compared with an outpatient group in an Asian population. However, given that the majority of patients in the inpatient cohort could tolerate sacubitril/valsartan, it would still be feasible to initiate this drug with close monitoring. Further randomised clinical trials in Asian populations are required to confirm this finding.

NT-proBNP Response to Sacubitril/Valsartan in Hospitalized Heart Failure Patients With Reduced Ejection Fraction: TRANSITION Study

ObjectivesThis study examined the effects of sacubitril/valsartan on N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels and determined patient characteristics associated with favorable NT-proBNP reduction response. BackgroundNT-proBNP levels reflect cardiac wall stress and predict event risk in patients with acute decompensated heart failure (ADHF). MethodsPost-hoc analysis of the TRANSITION (Comparison of Pre- and Post-discharge Initiation of Sacubitril/Valsartan Therapy in HFrEF Patients After an Acute Decompensation Event) study, including stabilized ADHF patients with reduced ejection fraction, randomized to open-label sacubitril/valsartan initiation in-hospital (pre-discharge) versus post-discharge. NT-proBNP was measured at randomization (baseline), discharge, and 4 and 10 weeks post-randomization. A favorable NT-proBNP response was defined as reduction to ≤1,000 pg/ml or >30% from baseline. ResultsIn patients receiving sacubitril/valsartan in-hospital, NT-proBNP was reduced by 28% at discharge, with 46% of patients obtaining favorable NT-proBNP reduction response compared with a 4% reduction and 18% favorable response rate in patients initiated post-discharge (p < 0.001). NT-proBNP was reduced similarly in patients initiating sacubitril/valsartan pre- and post-discharge (reduction at 4 weeks: 25%/22%; 10 weeks: 38%/34%) with comparable favorable response rates (46%/42% and 51%/48% at 4 and 10 weeks, respectively). NT-proBNP favorable response at 4 weeks was associated with lower risk of first heart failure (HF) rehospitalization or cardiovascular death through 26 weeks (hazard ratio: 0.57; 95% confidence interval [CI]: 0.38 to 0.86; p = 0.007). Predictors of a favorable response at 4 weeks were starting dose ≥49/51 mg twice daily, higher baseline NT-proBNP, lower baseline serum creatinine, de novo HF, no atrial fibrillation, angiotensin-converting enzyme inhibitor–naive or angiotensin receptor blocker–naive, and no prior myocardial infarction. ConclusionsIn-hospital initiation of sacubitril/valsartan produced rapid reductions in NT-proBNP, statistically significant at discharge. A favorable NT-proBNP response over time was associated with a better prognosis and predicted by higher starting dose and predisposing clinical profile. (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event [TRANSITION]; NCT02661217)

LCZ696 mitigates diabetic‐induced nephropathy through inhibiting oxidative stress, NF‐κB mediated inflammation and glomerulosclerosis in rats

BackgroundOne of the most common microvascular complications of diabetes is DN that considered the primary cause of end‐stage renal disease. Recently, combined therapy of angiotensin II receptor antagonist and neprilysin inhibitor are using to attenuate the DN. Thus the present study was designed to investigate the beneficial effects of LCZ696 (LCZ696) therapy on DN‐induced oxidative stress, inflammation and glomerulosclerosis in rats.MethodsA single dose (60 mg/kg/day) of STZ is used to induced type 1 diabetes. The diabetic rats were treated orally with valsartan (31 mg/kg) or LCZ696 (68 mg/kg) for 6 weeks. At end of the treatment period, serum and kidney samples were collected and analyzed. In serum, glucose, insulin, urea, creatinine, TNF‐α, IL‐1β, IL‐6 and IL‐10 levels were estimated. In renal tissues, oxidative stress biomarkers including TBARs, GSH, SOD, CAT, GPx and GST were measured. The levels of TNF‐α, IL‐1β, IL‐6 and NF‐kB levels also estimated in renal tissues. Histological changes were observed in kidney.ResultsDiabetic animals exhibited hyperglycemia and significant elevation in: renal functions, serum and kidney pro‐inflammatory cytokines, NF‐kB, lipid peroxidation, infiltration of leukocytes, mean glomerular volume and glomerulosclerosis with a marked decrease in IL‐10 and antioxidant enzymes. LCZ696 therapy significantly improved renal function and kidney structure and decreased oxidative stress, inflammation and glomerulosclerosis symptoms. Furthermore, valsartan alone had comparable effects against renal oxidative stress, inflammation and glomerulosclerosis.ConclusionTaken together, present data suggest that LCZ696 had therapeutic potential to restrict DN progression through inhibiting oxidative stress, NF‐kB mediated inflammation and glomerulosclerosis.

Sacubitril/Valsartan Therapy Ameliorates Ventricular Tachyarrhythmia Inducibility in a Rabbit Myocardial Infarction Model

BackgroundCoronary artery disease is the most common cause of heart failure (HF) in developed countries. The aim of this study was to elucidate the mechanisms of reduction of arrhythmias after sacubitril/valsartan (LCZ696) therapy in a myocardial infarction (MI)-HF rabbit model. Methods and ResultsChronic MI in rabbits with HF were divided into 3 groups: placebo control, valsartan 30 mg/day and LCZ696 60 mg/day. After 4 weeks of therapy, an electrophysiologic study and a dual voltage-calcium optical mapping study were performed. The LCZ696 group had significantly better left ventricular ejection fraction and lower ventricular tachyarrhythmia inducibility than the valsartan and placebo groups. The most common ventricular tachyarrhythmia pattern was 1 or 2 ectopic beats originating from the peri-infarct areas, followed by re-entrant beats surrounding phase singularity points. Compared to the valsartan and placebo groups, the LCZ696 group had significantly shorter action-potential duration, shorter intracellular calcium tau constant, faster conduction velocity, and shorter pacing cycle length to induce arrhythmogenic alternans. LCZ696 therapy reduced the phosphorylated calmodulin-dependent protein kinase II (CaMKII-p) expression. ConclusionsIn a rabbit model with chronic MI and HF, LCZ696 therapy ameliorated postinfarct heart function impairment and electrophysiologic remodeling and altered CaMKII-p expression, leading to reduced ventricular tachyarrhythmia inducibility.

1037 Differences in reverse remodelling between ischemic and non-ischemic left ventricular segments as assessed by myocardial work after sacubitril-valsartan therapy

Abstract Introduction Myocardial work (MW) is a new transthoracic echocardiographic (TTE) parameter that enhances the information provided through left ventricular (LV) global longitudinal strain (GLS), allowing to investigate LV performance even in cases of changes in afterload. None is known about the effects of Sacubitril-Valsartan (LCZ696) therapy in MW parameters. Purpose Compare the changes in MW parameters between ischemic and non-ischemic segments after LCZ696 therapy. Methods The study was a prospective evaluation of chronic Heart Failure (HF) patients with optimized standard of care therapy and LV ejection fraction ≤40%, in which LCZ696 therapy was started and no other HF treatment was expected to change. A TTE study was performed before and 6 months after LCZ696 therapy, using the GE Vivid E95 ultrasound system. A semiautomated analysis of GLS was performed after two-dimensional images were acquired in the standard apical 4-, 3- and 2 chamber views. MW and related indices were estimated using custom software. Two groups were created according to the 17 segment model TTE study before LCZ696 therapy: G1 (ischemic group): dyskinesia/akinesia/hypokinesia segments in patients with ischemic HF etiology; G2 (non-ischemic group): normokinesia segments in patients with ischemic and all segments in patients with non-ischemic HF etiology; Results Of the 42 patients, 35 (83.3%) completed the six-months follow-up with LCZ696, since 2 patients (4.8%) died and 5 patients (11.9%) discontinued treatment for adverse events. Mean age was 58.6 ± 11.1 years, with ischemic etiology in 15 (42.9%), resulting in a total of 26.5% segments for G1. Baseline global MW index (GWI) had no statistical difference between G1 and G2 (566.1 VS 584.8mmHg%, p = 0.257), but baseline MW efficiency (GWE) were significantly lower in G1 (71.9 VS 78.8%, p &amp;lt; 0.001). The table represents the mean values for MW parameters in G1 and G2 before and 6 months after LCZ696 therapy, with a significantly increase in GWI and GWE values in both groups. Despite no difference in the increase in GWE (p = 0.872), the increase in GWI were higher in G2 than G1 (p &amp;lt; 0.001). Conclusion MW seems to be a new tool providing signs of reverse remodelling and better cardiac performance in ischemic and non-ischemic segments after LCZ696 therapy. Table 1 Time 0 6 months p GWI in ischemic segments (mmHg%) 566.1 ± 364.0 696.5 ± 445.2 &amp;lt;0.001 GWE in ischemic segments (%) 71.9 ± 25.0 78.9 ± 19.1 0.009 GWI in non-ischemic segments (mmHg%) 584.8 ± 434.3 812.3 ± 442.0 &amp;lt;0.001 GWE in non-ischemic segments (%) 78.8 ± 21.2 85.7 ± 15.8 0.004 MW data before and after six months of LCZ696 therapy

P1433 Antiarrhythmic effects of sacubitril-valsartan therapy assessed by mechanical dispersion index

Abstract Introduction Sacubitril/Valsartan (LCZ696) significantly reduced sudden cardiac death in the PARADIGM-HF trial. However, there is little published data regarding the possible explanations for the antiarrhythmic effects found with LCZ696 therapy. Previous trials have shown that mechanical dispersion by strain echocardiography can predict arrhythmic events in Heart Failure (HF) patients. The aim of this study was to compare electrocardiographic (ECG) parameters and mechanical dispersion index with left ventricular (LV) global longitudinal strain (GLS) analysis before and after LCZ696 therapy. Methods Prospective evaluation of chronic HF patients with LV ejection fraction ≤ 40% despite optimized standard of care therapy, in which LCZ696 therapy was started and no additional HF treatment was expected to change. ECG and transthoracic echocardiographic data were gathered in the week before starting LCZ696 therapy and 6 months after therapy. A semiautomated analysis of LV GLS was made and mechanical dispersion index was defined as the standard deviation from the 16 time intervals corresponding to each LV segment. Results Of the 42 patients, 35 (83.3%) completed the 6 months of follow-up, since 2 (4.8%) patients died and 5 (11.9%) discontinued treatment for adverse events. Mean age was 58.6 ± 11.1 years. QTc interval (451.9 vs 426.0msec, p &amp;lt; 0.001) and QRS interval (125.1 vs 120.8msec, p = 0.033) were reduced after 6 months of LCZ696 therapy. Mechanical dispersion index (88.4 vs 78.1msec, p = 0.036) was also significantly reduced after therapy. Conclusion LCZ696 therapy is associated with antiarrhythmic effects with a reduction in QTc and QRS intervals in ECG and a reduction in mechanical dispersion index as assessed by LV GLS. Abstract P1433 Figure.

4940Early reverse remodelling assessed by myocardial work after sacubitril-valsartan therapy

Abstract Introduction Sacubitril/Valsartan (LCZ696) had prognosis benefit demonstrated in PARADIGM-HF trial, however less is known about his effects in cardiac dimensions and function. Myocardial work (MW) is a new transthoracic echocardiographic (TTE) parameter. None is known about the effects of LCZ696 therapy in MW parameters. Purpose The aim of this study was to prospectively compare several TTE parameters, including MW, before and after LCZ696 therapy. Methods Prospective evaluation of chronic HF patients with optimized standard of care therapy and LVEF≤40%, in which LCZ696 therapy was started. TTE study was performed before and 6 months after LCZ696 therapy. A semiautomated analysis of GLS was performed and MW were estimated using custom software of GE Vivid E95 ultrasound system. Results Of the 42 patients, 35 (83.3%) completed the 6 months follow-up, since 2 patients (4.8%) died and 5 patients (11.9%) discontinued treatment for adverse events. Mean age was 58.6±11.1 years with 82.9% of male patients. LV dimensions and atrial volumes were significantly lower at 6 months of treatment. LVEF had a mean absolute raise of 8.9% and GLS a relative decrease of 27.8%. MW had a significant increase in constructive work (720.2mmHg VS 900.6mmHg, p=0.016) and work efficiency (78.6% VS 86.6%, p=0.027), with a non-significant decrease in the wasted work (150.2mmHg VS 136.8mmHg, p=0.441). TTE data before and after 6 months of LCZ696 treatment Time 0 6 months p LV end-diastolic diameter (mm) 71.3±8.4 66.9±7.6 0.001 LV end-systolic diameter (mm) 57.8±9.4 53.1±9.3 0.002 Interventricular septum (mm) 9.6±1.7 9.9±1.9 0.280 LVEF (%) 29.3±6.4 38.2±8.9 &lt;0.001 GLS (%) −7.0±2.9 −8.9±2.8 0.001 MW – Constructive (mmHg) 720.2±230.5 900.6±343.2 0.016 MW – Wasted (mmHg) 150.2±83.3 136.8±54.2 0.441 MW – Efficiency (%) 78.6±10.8 86.6±12.0 0.027 E/e' 13.7±4.5 12.8±4.9 0.449 Pulmonary artery systolic pressure (mmHg) 38.3±12.2 30.9±10.6 &lt;0.001 Left atrium volume (ml/m2) 51.5±22.6 43.7±15.8 0.004 Right atrium volume (ml/m2) 33.1±4.4 28.5±13.5 0.036 TAPSE (mm) 19.2±4.4 20.0±4.9 0.404 Conclusion LCZ696 therapy is associated with signs of reverse remodelling in TTE, including an increase in constructive work and work efficiency.

LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model

Background LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. Methods We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. Results The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. Conclusion As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.

Antiarrhythmic Effect of Sacubitril-Valsartan: Cause or Consequence of Clinical Improvement?

Sacubitril/Valsartan (LCZ696) reduced sudden cardiac death in the PARADIGM-HF trial. However, the mechanism by which LCZ696 reduces ventricular arrhythmias remains unclear. The aim of this study was to compare electrocardiographic (ECG) parameters and mechanical dispersion index, assessed by left ventricular (LV) global longitudinal strain (GLS), before and after LCZ696 therapy. We prospectively evaluated chronic Heart Failure (HF) patients with LV ejection fraction ≤40%, despite optimal medical and device therapy, in which LCZ696 therapy was started, while no additional HF treatment was expected to change. ECG and transthoracic echocardiographic data were gathered in the week before starting LCZ696 and at six months of therapy. A semiautomated analysis of LV GLS was performed and mechanical dispersion index was defined as the standard deviation from 16 time intervals corresponding to each LV segment. Of the 42 patients, 35 completed the six month follow-up, since two patients died and five discontinued treatment for adverse events. QTc interval (451.9 vs. 426.0 ms, p < 0.001), QRS duration (125.1 vs. 120.8 ms, p = 0.033) and mechanical dispersion index (88.4 vs. 78.1 ms, p = 0.036) were significantly reduced at six months. LCZ696 therapy is associated with a reduction in QTc interval, QRS duration and mechanical dispersion index as assessed by LV GLS.

Neprilysin Inhibitors and Bradykinin.

Bradykinin has important physiological actions related to the regulation of blood vessel tone and renal function, and protection from ischemia reperfusion injury. However, bradykinin also contributes to pathological states such as angioedema and inflammation. Bradykinin is metabolized by many different peptidases that play a major role in the control of bradykinin levels. Peptidase inhibitor therapies such as angiotensin converting enzyme (ACE) and neprilysin inhibitors increase bradykinin levels, and the challenge for such therapies is to achieve the beneficial cardiovascular and renal effects without the adverse consequences such as angioedema that may result from increased bradykinin levels. Neprilysin also metabolizes natriuretic peptides. However, despite the potential therapeutic benefit of increased natriuretic peptide and bradykinin levels, neprilysin inhibitor therapy has only modest efficacy in essential hypertension and heart failure. Initial attempts to combine neprilysin inhibition with inhibition of the renin angiotensin system led to the development of omapatrilat, a drug that combines ACE and neprilysin inhibition. However, omapatrilat produced an unacceptably high incidence of angioedema in patients with hypertension (2.17%) in comparison with the ACE inhibitor enalapril (0.68%), although angioedema incidence was less in patients with heart failure with reduced ejection fraction (HFrEF) treated with omapatrilat (0.8%), and not different from that for enalapril therapy (0.5%). More recently, LCZ696, a drug that combines angiotensin receptor blockade and neprilysin inhibition, was approved for the treatment of HFrEF. The approval of LCZ696 therapy for HFrEF represents the first approval of long-term neprilysin inhibitor administration. While angioedema incidence was acceptably low in HFrEF patients receiving LCZ696 therapy (0.45%), it remains to be seen whether LCZ696 therapy for other conditions such as hypertension is also accompanied by an acceptable incidence of angioedema.

The relationship between natriuretic peptides and neprilysin pathways: the clinical simplification against the complexity of biological systems

A large body of evidence supports the use of natriuretic peptides (brain natriuretic peptide [BNP] and N-terminal proBNP [NT-proBNP]) for the evaluation and management of patients with heart failure over time. Elevated values reflect an enhanced counterregulatory response to hemodynamic stress and are indicative of heart failure severity, thus predicting prognosis. The clinical relevance and result interpretation of natriuretic peptides for monitoring therapy are still debated, and our understanding of their complex nature is still far from being complete. The new data about the clinical efficacy of LCZ696, a combination neprilysin inhibitor and angiotensin receptor blocker recently approved for the treatment of symptomatic chronic heart failure, showed a different susceptibility of BNP and NT-proBNP during therapy. The aim of this article is to discuss the controversial issues concerning the clinical use of cardiac natriuretic peptide measurement, the complex relationship with neprilysin pathways, and the practical implications of LCZ696 therapy for natriuretic peptide testing in clinical practice.

PP.11.16] THE COMBINATION DRUG VALSARTAN/SACUBITRIL (LCZ696) REDUCED PULSE WAVE VELOCITY AND AORTIC SYSTOLIC BLOOD PRESSURE IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION

Objective: Dual neprilysin inhibition and angiotensin receptor blockade with LCZ696 has been shown therapeutic benefits in chronic heart failure (CHF) patients. The aim of the study was to assess LCZ696 effects on parameters of arterial stiffness in stable heart failure with reduced ejection fraction (HFrEF). Design and method: In the open-label follow-up to PARADIGM HF study 18 patients with stable HFrEF (16 male, 69 ± 9 years (M ± SD), arterial hypertension 83%, previous myocardial infarction 89%, diabetes mellitus 39%, dyslipidemia 56%, LVEF 32 ± 4%, serum creatinine 118 ± 21 μmol/l, eGFR 56 ± 13 ml/min/1.73m2, potassium 4.45 ± 0.35 mmol/l) were enrolled. Patients received a stable background treatment for at least a month (ACEI 94%, beta-blockers 100%, aldosterone receptor antagonists 83.3%, loop diuretics 72.2%). ACEI treatment was interrupted for 36 h and replaced with LCZ696 100 or 200 mg (11 patients) BID according to baseline brachial BP (mean dose 185.7 ± 36.3 mg BID). Applanation tonometry was performed baseline and after 6 month LCZ696 therapy. Wilcoxon test was considered significant if p < 0.05. Results: Baseline brachial BP decreased from 137.1 ± 22.0/83.4 ± 11.8 to 120.5 ± 13.5/75.1 ± 9.3 mmHg (δ −16.6 ± 14.2/−8.3 ± 10.3 mmHg, p < 0.05), heart rate did not change (78 ± 12 vs 75 ± 15 beats/min (δ −2.7 ± 14.7 beats/min, p > 0.05). Valsartan/sacubitril therapy was associated with significant decrease of carotid-femoral pulse wave velocity (11.5 ± 2.9 vs 10.2 ± 2.9 m/s, p < 0.05), central systolic (125 ± 16 vs 116 ± 15 mmHg, p = 0.005) and diastolic (78 ± 7 vs 74 ± 9 mmHg, p < 0.05) blood pressure. Central pulse pressure (45 ± 11 vs 41 ± 16 mmHg), augmentation pressure (16 ± 7,1 vs 13,8 ± 8,4 mmHg), augmentation index (29 ± 7 vs 28 ± 11%), time to reflected wave (128 ± 8 vs 132 ± 7 ms) did not change significantly (p > 0.05 for all comparisons). Conclusions: In stable patients with heart failure with reduced ejection fraction 6 month valsartan/sacubitril therapy was associated with significant decrease of aortic systolic pressure and pulse wave velocity.