Rationale and methods of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF)

The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi. Methods: Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up. Results: Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0

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“…25 The preservation of endothelial integrity are currently on their way giving rise to a more profound mechanistic understanding. 30…”

Section: T a B L E 2 Correlation Between Bio-adm Mrmentioning

confidence: 99%

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure

Arfsten

Goliasch

Bartko

et al. 2020

Brit J Clinical Pharma

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“…The effects of ARNi are being testing also in ongoing clinical trials, in the setting of cardiac remodeling [140] and endothelial function ( Identifier: NCT03119623). Pre-clinical evidence about the use of ARNi in cardiac and vascular remodeling are promising.…”

Section: Therapeutic Interventions Targeting Npsmentioning

confidence: 99%

Cardiovascular Pleiotropic Effects of Natriuretic Peptides

Forte

Madonna

Schiavon

et al. 2019

IJMS

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Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water–salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.

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“…This trial monitored NT-proBNP levels and changes in cardiac remodeling based on various echocardiographic parameters including LVEF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and the ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e′) (p<0.001 for all). 28 The results of this study showed that the baseline median NT-proBNP concentration of 816 pg/mL was decreased to 455 pg/mL at 12 months (difference, p<0.001). 28 28 The fact that the majority of these changes were seen early in the trial, including changes in NT-proBNP at lower doses of sacubitril/valsartan, has important consequences for starting sacubitril/valsartan early in the disease course.…”

Section: Effects On Cardiac Remodeling and Aortic Stiffnessmentioning

confidence: 63%

“…28 The results of this study showed that the baseline median NT-proBNP concentration of 816 pg/mL was decreased to 455 pg/mL at 12 months (difference, p<0.001). 28 28 The fact that the majority of these changes were seen early in the trial, including changes in NT-proBNP at lower doses of sacubitril/valsartan, has important consequences for starting sacubitril/valsartan early in the disease course. The EVALUATE-HF trial (Study of Effects of Sacubitril/Valsartan versus Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction) in 2019 did not show any significant reduction in central aortic stiffness in patients with HFrEF when given sacubitril/valsartan as compared to enalapril.…”

Section: Effects On Cardiac Remodeling and Aortic Stiffnessmentioning

confidence: 63%

<p>Impact of Sacubitril/Valsartan on Patient Outcomes in Heart Failure: Evidence to Date</p>

Akbar

Kabra

Aronow

2020

TCRM

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With an estimated 6.2 million adults affected in the USA, heart failure remains a leading cause of morbidity, mortality, and health-care costs, despite the use of guidelinebased medical therapies. The search for a more efficient therapy was rekindled when findings from the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial demonstrated evidence for cardiovascular and mortality benefit of sacubitril/valsartan, a dual angiotensin receptor blocker and neprilysin inhibitor (ARNI), over enalapril (an angiotensin-converting enzyme inhibitor) in patients with heart failure and reduced rjection fraction (HFrEF). Following the trial's compelling results, recommendations for the use of sacubitril/valsartan as a replacement for an angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker were incorporated into the 2016 American College of Cardiology (ACC), the American Heart Association (AHA), and the Heart Failure Society of America recommended (HFSA) guidelines for the management of heart failure. This review aims to gain insight into the benefits as well as limitations associated with the use of sacubitril/valsartan in the treatment of heart failure (HF) through exploration of various subgroup analyses of the PARADIGM-HF trial, subsequent retrospective analyses, and randomized controlled trials that followed this landmark trial.

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Rationale and methods of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF)

Cited by 75 publications

References 31 publications

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin‐receptor/neprilysin‐inhibitor treatment in chronic systolic heart failure

Cardiovascular Pleiotropic Effects of Natriuretic Peptides

<p>Impact of Sacubitril/Valsartan on Patient Outcomes in Heart Failure: Evidence to Date</p>

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