Author + information
- Chayakrit Krittanawong, MD∗ ( and )
- Takeshi Kitai, MD, PhD
- ↵∗Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, Mount Sinai St. Luke's and Mount Sinai West Hospitals, 1000 10th Avenue, New York, New York 10019
We read with great interest the recent paper by Troncone et al. (1), which highlighted the heart-to-brain amyloid hypothesis. The investigators suggested that heart failure (HF) shares several risk factors with Alzheimer's disease (AD), and that these 2 diseases perhaps share a common pathogenesis via a mechanism of amyloid-β (Aβ) regulation. Neprilysin, a plasma membrane metalloendopeptidase, is a major enzyme responsible for Aβ degradation, and animal studies have shown that inhibiting neprilysin results in increases in the levels of Aβ in the brain (2,3). The 2016 American College of Cardiology/American Heart Association/Heart Failure Society of America Focused Update on New Pharmacological Therapy for Heart Failure (4) recommended an angiotensin-receptor/neprilysin inhibitor (ARNI) for patients with HF with a reduced ejection fraction who tolerate an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker (ARB) to reduce morbidity and mortality. The guideline is recommended as Level of Evidence: B-R from the results of the PARADIGM-HF (Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure) trial (NCT01035255) (4). According to the PARADIGM-HF trial, ARNI had an acceptable safety profile over a median follow-up of 27 months. The trial was stopped early due to positive treatment effects, and it was not long enough to detect any differences in long-term side effects. Therefore, potential long-term side effects of ARNI remain unknown.
ARNI consists of an ARB and a neprilysin inhibitor, in a 1:1 mixture by molecule count. An inhibition of neprilysin increases the levels of substances (i.e., atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, bradykinin, substance P, and adrenomedullin) associated with vasodilatation, low blood pressure, and natriuresis and/or diuresis. However, inhibiting neprilysin may also increase the levels of Aβ in the brain, leading to the accumulation of Aβ plaques and AD.
Although ARB has benefit for neuroprotection (5), a neprilysin inhibitor may increase the risk of AD in some patients, particularly patients with risk factors of AD. Patients with HF have multiple risk factors (i.e., advancing age, hypertension, diabetes, hypercholesterolemia, and cerebrovascular disease) for AD. Thus, physicians should carefully monitor long-term therapy in HF patients who have risk factors of AD and be aware of potential side effects (i.e., AD). We agree with the investigators that further studies are needed to determine the dysfunctional cardiac phenotype observed in patients with AD. However, we would suggest that potential biomarkers (i.e., plasma neprilysin concentrations) need to be evaluated to characterize dysfunctional cardiac phenotypes in patients with AD. This may help shed light on the complex mechanism of Aβ and neprilysin regulation in the context of the heart-to-brain connection in patients with AD.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
- Troncone L.,
- Luciani M.,
- Coggins M.,
- et al.
- Yancy C.W.,
- Jessup M.,
- Bozkurt B.,
- et al.
- Fournier A.,
- Messerli F.H.,
- Achard J.M.,
- et al.