Angiotensin Receptor and Neprilysin Inhibitors for COVID-19 Treatment and Personalized Medicine?

We read with interest the expert review by Rex et al. (2021) suggesting that targeting angiotensin-converting enzyme and neprilysin may offer beneficial clinical outcomes in patients with coronavirus disease 2019 (COVID-19), especially in relation to the cardiovascular and renal function. Importantly, sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) can reduce the concentration of pro-inflammatory cytokines, and hence could counteract the cytokine storm associated with COVID-19. This letter aims to build and expand on this subject with an eye to concisely discuss the subpopulation of patients with COVID-19 in whom ARNI could offer benefits. This can also inform design of personalized medicines for COVID-19 in the future.

Higher concentrations of the N-terminal pro-brain natriuretic peptide (NT-proBNP) has been linked to COVID-19 fatality. Indeed, the association was recently confirmed by a prospective study (O'Donnell et al., 2021) in a large cohort of patients with COVID-19 (n = 4675). An elevated NT-proBNP level at baseline was significantly associated with higher odds of death (odds ratio = 2.23; 95% confidence interval: 1.80–2.76), after adjustment for covariates. The association held true in the subgroup analysis of patients without a history of heart failure (38% in patients with elevated NT-proBNP level vs. 16% in patients with normal NT-proBNP level; p < 0.001) (O'Donnell et al., 2021). In addition, an elevated NT-proBNP level at baseline was associated with the risk of development of new acute heart failure (6.0% in patients with elevated NT-proBNP level vs. 2.2% in patients with normal NT-proBNP level; p < 0.001) (O'Donnell et al., 2021).

We think elevated NT-proBNP levels may identify a subgroup of patients in need of cardioprotective therapy with ARNI. In fact, a recent autopsy study (Zhang et al., 2021) of heart tissue from the deceased patients with COVID-19 showed that active myocarditis was commonly infiltrated with neutrophils, indicating that neutrophils may be responsible for the development of cardiac injury in patients with COVID-19. Notoriously, “neutrophil burst” has been previously characterized by cytokine release, the increased release of reactive oxygen species (ROS), and the formation of neutrophil extracellular traps, which could lead to apoptosis and necrosis of myocardial cells. With BNP being known as a negative modulator of the neutrophil burst, their elevation in patients with COVID-19 as reported in the literature, especially those with cardiac injury, comes as no surprise.

Although BNP acts as a substantial negative modulator of ROS release by neutrophils, there may be impairment of the antioxidant effects of BNP at the neutrophil level, due to the degradation of BNP by neutral endopeptidase (neprilysin) within neutrophils (Matsumura et al., 1996). This has been reported to occur in patients with chronic heart failure, which leads to the introduction of ARNI (sacubitril/valsartan) for clinical use in this population of patients, and with favorable effects. With significant expression of neprilysin being found on neutrophils, the reduced antioxidant activities of BNP could also occur in patients with COVID-19, especially in patients with severe disease, subsequently leading to disease progression and heightened risk of death as reported.

Taken together, we suggest here that ARNI therapy can be useful in patients with COVID-19, and particularly those with elevated NT-proBNP levels, thereby offering rationales for the prospect of stratified/personalized medicine algorithms in the future. In the landmark Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study, ARNI therapy (sacubitril/valsartan) resulted in a decrease of NT-proBNP and increase of BNP levels, respectively (McMurray et al., 2014). We think ARNI therapy warrants a clinical trial in patients with COVID-19 and elevated NT-proBNP level. This would help determine if it could reduce the risk of death and cardiovascular complications, in combination with anti-inflammatory therapies.