Angiotensin receptor neprilysin inhibition versus individualized RAAS blockade: design and rationale of the PARALLAX trial

Wachter, Rolf; Shah, Sanjiv J.; Cowie, Martin R.; Szecsödy, Peter; Shi, Victor; Ibram, Ghionul; Zhao, Zhenlu; Gong, Jianjian; Klebs, Sven; Pieske, Burkert

doi:10.1002/ehf2.12694

Cited by 37 publications

(55 citation statements)

References 27 publications

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“…Nevertheless, subgroup analyses of this trial suggest beneficial effects in patients with mildly reduced LVEF and females, suggesting a benefit of Sac/Val in specific subgroups [ 15 ]. Very recently, preliminary data from the PARALLAX-HF trial demonstrated superiority of Sac/Val compared to individualized medical therapy in the reduction of NT-proBNP levels associated with a lower clinical event rate [ 16 ]. Beyond a possible clinical impact of Sac/Val in HFpEF, the underlying pathophysiological mechanisms of Sac/Val treatment within the HFpEF syndrome are incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Sacubitril/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF

Schauer

Adams

Augstein

et al. 2021

IJMS

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The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.

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Section: Introductionmentioning

confidence: 99%

Sacubitril/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF

Schauer

Adams

Augstein

et al. 2021

IJMS

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“…The SILICOFCM trial (60) (NCT03832660), will provide insights into the effect of sacubitril/valsartan in patients with nonobstructive hypertrophic cardiomyopathy. Functional outcomes are equally important such as quality of life, symptom burden and exercise capacity, all of which will be measured in the PARALLAX study comparing sacubitril/valsartan with standard of care (61).…”

Section: Future Directions and Ongoing Trialsmentioning

confidence: 99%

Narrative review in the current role of angiotensin receptor-neprilysin inhibitors

Rodríguez¹,

Cu²,

Siddiqui³

2021

Ann Transl Med

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Heart failure (HF) accounts for a tremendous burden on health care systems and the society.Since the landmark PARADIGM-HF trial, sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitor (ARNI) showed superiority to enalapril in patients with HF with reduced ejection fraction (HFrEF). We performed a narrative literature review, hand-searched the reference lists of included articles and relevant reviews. Inhibition of neprilysin increases bradykinin, natriuretic peptides and adrenomedullin levels counteract the neurohormal activation that leads to sodium retention, vasoconstriction, and cardiac remodeling. In PARADIGM-HF the primary outcome of CV death or HF hospitalization was reduced 20% in the ARNI group (HR 0.80, P<0.001) similar to mortality due to cardiovascular cause (HR 0.80, P<0.001) in patients with HFrEF, rendering a number needed to treat of 21 patients. This effect was consistent across subgroups. The safety of starting ARNI inpatient once the acute decompensation of HF is stabilized was demonstrated in PIONEER-HF trial. With willingness-topay thresholds commonly acceptable in the United States, sacubitril/valsartan is likely to be cost effective, which might not be in other health systems. Although its safety has been reassured in some clinical trials, common side effects are hypotension, worsening kidney function, hyperkalemia and angioedema. In HFpEF (PARAGON-HF), sacubitril/valsartan showed decrease in the level of the cardiac biomarkers, with improve functional NYHA and decrease in hospitalizations, predominately in women and patients with borderline ejection fraction. Some ongoing studies aim to demonstrate the effects of ARNI in acute coronary syndrome, stable ischemic heart disease, advanced HF, mitral regurgitation, aortic impedance and pulmonary hypertension. In conclusion, sacubitril/valsartan has proven to be an effective addition to the HFrEF arsenal, with safety comparable to current standard of care. In HFpEF, it improves quality of life, particularly in women and in patients with borderline ejection fraction, with no effect on mortality.

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“…While there was no effective therapeutic methods to improve the prognosis of HFpEF to date ( 7 ). Recently, a novel study named PARALLAX trial show that sacubitril/valsartan can ameliorate the outcome of HFpEF, but it needs more investigations to confirm the theory ( 8 ). According to these situations, it is necessary to find new therapeutic methods for HFpEF.…”

Section: Introductionmentioning

confidence: 99%

Early Passive Leg Movement Prevents Against the Development of Heart Failure With Preserved Ejection Fraction in Rats

Liu

et al. 2021

Front. Cardiovasc. Med.

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Exercising was reported by several studies to bring great benefits to heart failure with preserved ejection fraction (HFpEF), which reduced the hospitalization and the mortality of heart failure. However, the underlying mechanism of exercising on HFpEF remains unclear. In the present study, we designed and constructed a device that can perform early passive leg movement (ePLM) in rats and further observed whether treatment of ePLM exerts protective effects on HFpEF of rats. Rats were fed with high salt feed to establish an animal model of pre-clinical diastolic dysfunction (PDD), which would eventually develop into HFpEF, and then treated rats with ePLM. We conducted several experiments to evaluate the conditions of heart and blood vessel. The results show that diastolic functions of heart and blood vessel in rats were significantly improved by treatment of ePLM. We also found that pathological injuries of heart and blood vessel were ameliorated after treatment of ePLM. Moreover, treatment of ePLM decreased the protein levels of Collagen type I, Collagen type III, MMP2, and MMP9 in heart and blood vessel, indicating that cardiac and vascular fibrosis were reduced apparently by treatment of ePLM. Further investigation suggested that treatment of ePLM probably inhibit the activation of TGF-β1/Smad3 signaling pathway as well as promote the activation of Akt/eNOS signaling pathway in high salt diet induced HFpEF. In conclusion, treatment of ePLM alleviated high salt diet induced HFpEF by inhibiting fibrosis via suppressing TGF-β1/Smad3 signaling pathway as well as activating Akt/eNOS signaling pathway, implicating treatment of ePLM as a promising novel non-pharmacological approach for HFpEF.

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Angiotensin receptor neprilysin inhibition versus individualized RAAS blockade: design and rationale of the PARALLAX trial

Cited by 37 publications

References 27 publications

Sacubitril/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF

Sacubitril/Valsartan Improves Diastolic Function But Not Skeletal Muscle Function in a Rat Model of HFpEF

Narrative review in the current role of angiotensin receptor-neprilysin inhibitors

Early Passive Leg Movement Prevents Against the Development of Heart Failure With Preserved Ejection Fraction in Rats

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