The development of the agent Sacubitril / Valsartan ( Entresto ), known as an angiotensin receptor blocker-neprilysin inhibitor ( ARNI ), to improve heart failure ( HF ) management, may benefit morbidity, mortality, and readmission rates in patients with heart failure.

The PARADIGM-HF trial demonstrated that the ARNI can reduce morbidity and mortality in patients with heart failure with reduced ejection fraction ( HFrEF ), while ongoing PARAMOUNT and PARAGON-HF trials determined whether the ARNI has morbidity and mortality benefits in patients with heart failure with preserved ejection fraction ( HFpEF ).

However, the risk of long-term side effects of the ARNI such as cognitive dysfunction or Alzheimer's disease remains unknown.
In fact, neprilysin ( NEP ), encoded by NEP or MME gene, is a principal peptidase involved in the degradation of beta-amyloid protein.

Several studies have demonstrated that polymorphisms of the NEP gene may be associated with Alzheimer's disease and cerebral amyloid angiopathy (CAA).

Pharmacogenomics, the study of variability in drug response due to genetic polymorphisms, can potentially explain the variability in the effect of the ARNI and their side effects.

Physicians should carefully monitor elderly patients with genetic risk factors for Alzheimer's disease and cerebral amyloid angiopathy.
In the future, genetic testing and genomic testing for NEP polymorphisms may play an important role in monitoring long-term side effects in ARNI-treated heart failure patients. ( Xagena )

Krittanawong C, Kitai T, Cardiovasc Ther 2017;35(4). doi: 10.1111/1755-5922.12272.

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