Natriuretic Peptides as Biomarkers: Narrative Review and Considerations in Cardiovascular and Respiratory Dysfunctions.

Natriuretic peptides (NPs) encompass a family of structurally related hormone/paracrine factors acting through the natriuretic peptide system regulating cell proliferation, vessel tone, inflammatory processes, neurohumoral pathways, fluids, and electrolyte balance. The three most studied peptides are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-Type natriuretic peptide (CNP). ANP and BNP are the most relevant NPs as biomarkers for the diagnosis and prognosis of heart failure and underlying cardiovascular diseases, such as cardiac valvular dysfunction, hypertension, coronary artery disease, myocardial infarction, persistent arrhythmias, and cardiomyopathies. Cardiac dysfunctions related to cardiomyocytes stretching in the atria and ventricles are primary elicitors of ANP and BNP release, respectively. ANP and BNP would serve as biomarkers for differentiating cardiac versus noncardiac causes of dyspnea and as a tool for measuring the prognosis of patients with heart failure; nevertheless, BNP has been shown with the highest predictive value, particularly related to pulmonary disorders. Plasma BNP has been reported to help differentiate cardiac from pulmonary etiologies of dyspnea in adults and neonates. Studies have shown that COVID-19 infection also increases serum levels of N-terminal pro b-type natriuretic peptide (NT-proBNP) and BNP. This narrative review assesses aspects of ANP and BNP on their physiology, and predictive values as biomarkers. We present an overview of the NPs' synthesis, structure, storage, and release, as well as receptors and physiological roles. Following, considerations focus on ANP versus BNP, comparing their relevance in settings and diseases associated with respiratory dysfunctions. Finally, we compiled data from guidelines for using BNP as a biomarker in dyspneic patients with cardiac dysfunction, including its considerations in COVID-19.

Elevated Natriuretic Peptides in Patients With Severe or Critical COVID-19: A Meta-Analysis.

BACKGROUND: The worldwide COVID-19 pandemic caused by SARS-CoV-2 has resulted in an extraordinary increase in the number of patients who are severely critically ill. For many of these patients, cardiovascular risk factors are key contributors to the development of severe illness. Laboratory markers for cardiac damage and failure, such as natriuretic peptides, are reported to be elevated in patients with severe COVID-19. METHODS: We conducted a systematic review and meta-analysis to compare natriuretic peptide levels in patients with severe COVID-19 vs those with nonsevere COVID-19. PubMed and medRxiv were searched through April 7, 2020. The outcome of interest was the difference in B-type natriuretic peptide (BNP) or N-terminal-proBNP levels in patients with severe vs nonsevere COVID-19. RESULTS: We identified 9 retrospective cohort studies that had a total of 1,575 patients with COVID-19 who had their natriuretic peptides measured and were classified by disease severity. All studies were conducted in China. Patients with severe COVID-19 had significantly higher BNP levels than patients with nonsevere COVID-19 (mean difference, 69.56 pg/mL; 95% CI, 1.77-137.35 pg/mL; P = .04, I2 = 83%). Similarly, patients with severe COVID-19 had significantly higher N-terminal-proBNP levels than patients with nonsevere COVID-19 (mean difference, 518.65 pg/mL; 95% CI, 152.40-884.90 pg/mL; P = .006, I2 = 86%). CONCLUSIONS: In this study, Chinese patients with severe COVID-19 had higher natriuretic peptide levels than those with nonsevere COVID-19. Studies from all countries affected by the virus will help to further delineate whether the cause is directly or indirectly of cardiac origin and whether preexisting heart failure has an influence on this disparity.

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.

Coronavirus disease 2019 in patients with cardiovascular disease: clinical features and implications on cardiac biomarkers assessment.

INTRODUCTION: Previous cardiovascular disease (CVD) and myocardial involvement are common in coronavirus disease-19 (COVID-19). We investigated relationships between CVD, cardiac biomarkers and outcome in COVID-19. METHODS: We analyzed n = 252 patients from a multicenter study and provided comparison according to the presence or absence of underlying CVD. Cardiac biomarkers high-sensitivity Troponin [upper reference of normality (URN) 35 pg/ml for Troponin I and 14 pg/ml for Troponin T] and natriuretic peptides (Nt-pro-B-type natriuretic peptide, URN 300 pg/ml and B-type natriuretic peptide, URN 100 pg/ml) were both available in n = 136. RESULTS: Mean age was 69 ±â€Š16 years (56% men, 31% with previous CVD). Raised hs-Troponin and natriuretic peptides were detected in 36 and 50% of the cases respectively. Age, chronic obstructive pulmonary disease, hemoglobin, hs-Troponin and natriuretic peptides were independently associated with underlying CVD (P < 0.05 for all). Compared with the normal biomarkers subgroups, patients with isolated hs-Troponin elevation had higher in-hospital mortality (31 vs. 4%, P < 0.05), similar CVD prevalence (15 vs. 11%) and trend towards higher D-dimer (930 vs. 397 ng/ml, P = 0.140). Patients with both biomarkers elevated had higher age, D-dimer, CVD and in-hospital mortality prevalence compared with other subgroups (all P < 0.05 for trend). Outcome analysis revealed previous CVD [model 1: OR 2.72 (95% CI 1.14-6.49), P = 0.024. model 2: OR 2.65 (95% CI 1.05-6.71), P = 0.039], hs-Troponin (log10) [OR 2.61 (95% CI 1.21-5.66), P = 0.015] and natriuretic peptides (log10) [OR 5.84 (95%CI 2.43-14), P < 0.001] to be independently associated with in-hospital mortality. CONCLUSION: In our population, previous CVD was part of a vulnerable phenotype including older age, comorbidities, increased cardiac biomarkers and worse prognosis. Patients with isolated increase in hs-Troponin suffered higher mortality rates despite low prevalence of CVD, possibly explained by higher COVID-19-related systemic involvement.

Incidence and determinants of high-sensitivity troponin and natriuretic peptides elevation at admission in hospitalized COVID-19 pneumonia patients.

BACKGROUND: Myocardial involvement in the course of coronavirus disease 2019 (COVID-19) pneumonia has been reported, though not fully characterized yet. The aim of the present study is to undertake a joint evaluation of hs-Troponin and natriuretic peptides (NP) in patients hospitalized for COVID-19 pneumonia. METHODS: In this multicenter observational study, we analyzed data from n = 111 patients. Cardiac biomarkers subgroups were identified according to values beyond reference range. RESULTS: Increased hs-Troponin and NP were found in 38 and 56% of the cases, respectively. As compared to those with normal cardiac biomarkers, these patients were older, had higher prevalence of cardiovascular diseases (CVD) and had more severe COVID-19 pneumonia by higher CRP and D-dimer and lower PaO2/FIO2. Two-dimensional echocardiography performed in a subset of patients (n = 24) showed significantly reduced left ventricular ejection fraction in patients with elevated NP (p = 0.02), whereas right ventricular systolic function (tricuspid annular plane systolic excursion) was significantly reduced both in patients with high hs-Troponin and NP (p = 0.022 and p = 0.03, respectively). Both hs-Troponin and NP were higher in patients with in-hospital mortality (p = 0.001 and p = 0.002, respectively). On multivariable analysis, independent associations were found of hs-Troponin with age, PaO2/FIO2 and D-dimer (B = 0.419, p = 0.001; B = - 0.212, p = 0.013; and B = 0.179, p = 0.037, respectively) and of NP with age and previous CVD (B = 0.480, p < 0.001; and B = 0.253, p = 0.001, respectively). CONCLUSIONS: Myocardial involvement at admission is common in COVID-19 pneumonia. Independent associations of hs-Troponin with markers of disease severity and of NP with underlying CVD might point toward existing different mechanisms leading to their elevation in this setting.

value of cardiac biomarkers in COVID-19 disease / Valor pronóstico de biomarcadores cardíacos en la enfermedad por COVID-19

Resumen Introducción: En la enfermedad por COVID-19 se ha establecido que los pacientes con enfermedad cardiometabólica de base tienen mayor riesgo de presentar desenlaces adversos. Esto ha incrementado el interés en estudiar variables cardiovasculares relevantes, para plantear su correlación con los desenlaces clínicos en esta población. Objetivo: Describir el valor pronóstico de los biomarcadores cardíacos en la enfermedad por COVID-19. Métodos: Revisión no sistemática de la literatura en bases de datos como PubMed, Google Scholar, Clinical Key, SciELO, entre otras, utilizando palabras clave, términos planos y términos MeSh. Resultados: Se eligieron 22 bibliografías, entre ellas artículos de revisión de tema, revisiones sistemáticas, metaanálisis, estudios observacionales y artículos originales publicados hasta la fecha (mayo 13 de 2020), que en su mayoría describen la alteración de biomarcadores cardiacos y su relación con la evolución clínica de los pacientes con COVID-19. Discusión: Se encontró que la troponina y el péptido natriurético se comportan como factores de riesgo independientes para compromiso clínico severo, requerimiento de soporte ventilatorio o hemodinámico, estancia en la UCI, y aumento de la mortalidad. Conclusiones: Es razonable plantear el uso de estos biomarcadores en la estratificación del riesgo en pacientes con COVID-19 y enfermedad cardiovascular establecida.

Abstract Introduction: It has been established that patients with an underlying cardiometabolic disease and COVID-19 infections, have a higher risk of an adverse outcome. This has led to an increase in the interest of studying relevant cardiovascular variables, in order to establish their association with clinical outcomes in this population. Objective: To describe the prognostic value of cardiac biomarkers in disease caused by COVID-19. Methods: A non-systematic review of the literature was carried out in data bases that included PubMed, Google Scholar, Clinical Key, SciELO, using the key words, plain terms, and MeSH terms. Results: A total of 22 articles were chosen. They consisted of review articles on the subject, systematic reviews, meta-analyses, observational studies, and original articles published up until 13 May 2020. The majority of them described the changes in cardiac biomarkers and their relationship with the clinical outcome of patients COVID-19. Discussion: It was found that Troponin and Natriuretic Peptide behaved as independent risk factors for severe clinical compromise, requiring ventilatory or haemodynamic support, admission to ICU, and an increase in mortality. Conclusions: It is reasonable to recommend the use of these biomarkers in the risk stratification in patients with COVID-19 and an established cardiovascular disease.

The role of natriuretic peptide estimation in severe COVID-19.

Since its inception in Wuhan in December 2019, Coronavirus disease 2019 (COVID-19) has shattered the economies and health-care infrastructures worldwide. Even the best of health-care systems (United States, Italy) have been overwhelmed and collapsed because of this unprecedented pandemic. India is preparing itself for the onslaught of Coronavirus. After recording its first case on January 30th, 2020, the rise was slow until the last week of March. However, since then, the number of cases has increased exponentially, and as on April 14th, 2020, there have been more than 10,000 cases of coronavirus disease (COVID-19) in India, which has resulted in more than 350 deaths.