Targeting and Modulation of the Natriuretic Peptide System in Covid-19: A Single or Double-Edged Effect?

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19.

Chronic use of renin-angiotensin-aldosterone inhibitors in hypertensive COVID-19 patients: Results from a Spanish registry and meta-analysis.

BACKGROUND: Hypertension is a prevalent condition among SARS-CoV-2 infected patients. Whether renin-angiotensin-aldosterone system (RAAS) inhibitors are beneficial or harmful is controversial. METHODS: We have performed a national retrospective, nonexperimental comparative study from two tertiary hospitals to evaluate the impact of chronic use of RAAS inhibitors in hypertensive COVID-19 patients. A meta-analysis was performed to strengthen our findings. RESULTS: Of 849 patients, 422 (49.7%) patients were hypertensive and 310 (73.5%) were taking RAAS inhibitors at baseline. Hypertensive patients were older, had more comorbidities, and a greater incidence of respiratory failure (-0.151 [95% CI -0.218, -0.084]). Overall mortality in hypertensive patients was 28.4%, but smaller among those with prescribed RAAS inhibitors before (-0.167 [95% CI -0.220, -0.114]) and during hospitalization (0.090 [-0.008,0.188]). Similar findings were observed after two propensity score matches that evaluated the benefit of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers among hypertensive patients. Multivariate logistic regression analysis of hypertensive patients found that age, diabetes mellitus, C-reactive protein, and renal failure were independently associated with all-cause mortality. On the contrary, ACEIs decreased the risk of death (OR 0.444 [95% CI 0.224-0.881]). Meta-analysis suggested a protective benefit of RAAS inhibitors (OR 0.6 [95% CI 0.42-0.8]) among hypertensive COVID-19. CONCLUSION: Our data suggest that RAAS inhibitors may play a protective role in hypertensive COVID-19 patients. This finding was supported by a meta-analysis of the current evidence. Maintaining these medications during hospital stay may not negatively affect COVID-19 outcomes.