Preoperative Natriuretic Peptides in Noncardiac Surgery

Abstract

Cardiac risk evaluation is a central component of most preoperative evaluation of adults undergoing noncardiac surgery. Many tools are available for preoperative cardiac assessment including cardiac risk scores, electrocardiogram, cardiac imaging, and cardiac stress tests. Biomarkers, and more specifically natriuretic peptides, have also been found to provide additional value for preoperative cardiac risk stratification and their routine use in at-risk patients have been recommended in recent perioperative guidelines. RÉSUMÉ L évaluation des risques cardiaques est un élément central de la plupart des évaluations préopératoires des adultes subissant une chirurgie non cardiaque. De nombreux outils sont disponibles pour l évaluation cardiaque préopératoire, notamment les scores de risque cardiaque, l électrocardiogramme, l imagerie cardiaque et les tests d effort cardiaque. On a également constaté que les biomarqueurs, et plus particulièrement les peptides natriurétiques, apportent une valeur supplémentaire pour la stratification du risque cardiaque préopératoire et leur utilisation systématique chez les patients à risque a été recommandée dans de récentes lignes directrices périopératoires Introduction Cardiac risk evaluation is a central component of most preoperative evaluation of adults undergoing noncardiac surgery. Many tools are available for preoperative cardiac assessment including cardiac risk scores, electrocardiogram, cardiac imaging, and cardiac stress tests. Biomarkers, and more specifically natriuretic peptides, have also been found to provide additional value for preoperative cardiac risk stratification and their routine use in at-risk patients have been recommended in recent perioperative guidelines.1,2 In this review, we will provide an overview of the physiological and analytic considerations regarding natriuretic peptides, discuss their utility for preoperative cardiac risk stratification in addition to clinical evaluation, and discuss indications for preoperative natriuretic peptides testing. We will also address the potential benefit of natriuretic peptides testing in patients with cardiovascular disease and discuss conditions associated with elevated natriuretic peptides that are relevant to the perioperative setting. C a n a d i a n J o u r n a l o f G e n e r a l I n t e r n a l M e d i c i n e V o l u m e 1 6 , S p e c i a l I s s u e 1 , 2 0 2 1 43 D u c e p p e a n d D u r a n d CJGIM_1_2021_176993.indd 43 3/22/21 6:29 PM The Heart: An Endocrine Organ Almost 40 years ago, it was first reported that atrial myocardium extracts contained biologically active peptides that when injected to non-diuretic rats, induced a rapid and potent natriuresis and diuresis, along with potassium excretion.3 Following this original observation, this field of research evolved to revise the role of the heart as no longer a mere valve-and-muscle pump, but a complex organ that exerts an endocrine function, playing a key role in cardiovascular and renal regulation.4 Cardiac natriuretic hormones include atrial natriuretic peptide and brain natriuretic peptide (BNP) and are predominantly produced by cardiomyocytes. BNP mainly originates from ventricles and is released as a prohormone, proBNP, which is subsequently split into the inactive N-terminal peptide (NT-proBNP), and the active hormone, BNP.5 Both peptides are released in equimolar proportions and represent the same hormonal activity. However, because of different clearance mechanisms, of which 15–20% is by the kidneys, BNP has a halflife of 20 min and NT-proBNP of 120 min and NT-proBNP serum concentrations are approximatively six times higher than BNP.5–7 Electron microscopy of ventricular cardiomyocytes show that under physiological conditions (i.e., a healthy heart), secretory granules of proBNP are found only in limited amounts.4 On the other hand, markedly high levels of natriuretic peptides found in patients with chronic heart failure suggest a resistance to the biological effects of BNP, which at such high levels is no longer biologically active.4,8 Several pathophysiological mechanisms increase production and release of BNP, including mechanical, inflammatory, ischemic, hemodynamic, and other humoral stimuli.4 Ventricular stretch and mechanical strain were initially considered the main mechanisms for increased BNP production and release.9 Angiotensin-II,5 arginine vasopressin,10 and α-adrenergic agents11 are some of the peptides involved in hemodynamic response that have been found to stimulate BNP production/release. Proinflammatory and inflammatory response factors such as endothelin-1,12 cytokines (i.e., interleukin-1, interleukin-6, tumor necrosis factor-α),13 and prostaglandins14 all up-regulate the expression of BNP. Thyroid hormones,15 corticosteroids,15 and estrogens16 also increase BNP; conversely, androgens inhibit BNP production, likely explaining small sex variation that can be observed in BNP/NT-proBNP levels.17 Another important mechanisms leading to BNP/NT-proBNP release is myocardial hypoxia, ischemia, and fibrosis.5,18 Natriuretic Peptides as an Alternative to Cardiac Imaging for Preoperative Cardiac Risk Stratification Biomarker use for cardiac risk stratification in the perioperative setting has gained interest in the recent decades and BNP/ NT-proBNP have the most compelling evidence for their use in clinical practice.1 They offer an alternative to cardiac imaging (e.g., echocardiogram, cardiac stress testing) that is less expensive and does not require patients to come back to the hospital, potentially avoiding surgical delays. Park et al.19 compared the predictive performance of a preoperative echocardiogram and NT-proBNP in addition to clinical evaluation using the Revised Cardiac Risk Index (RCRI)20—a commonly used clinical risk score—to predict postoperative major cardiac events (PMCE) after noncardiac surgery. The authors found that compared to an RCRI score ≥2 (relative risk [RR] 1.35, 95% confidence interval [CI] 1.02–1.76), adding echocardiography findings of left ventricular ejection fraction (LVEF) <50% resulted in only minimal change in risk prediction (RCRI + LVEF: RR 1.82, 95% CI 1.39–2.35). In contrast, the addition of an elevated preoperative NT-proBNP ≥301 ng/L to RCRI was associated with a significantly higher risk of PMEC (RCRI + NT-proBNP: RR 3.72, 95% CI 2.73–4.96). A reduced LEVF added to both RCRI and NT-proBNP did not result in a meaningful change in risk prediction (RCRI + NT-proBNP + LEVF: RR 3.96, 95% CI 2.88–5.33). Many studies have looked at the prognostic value of preoperative cardiac stress testing (i.e., stress echocardiogram and nuclear stress testing) but none have looked at the risk prediction improvement beyond the use of clinical risk scores or compared to BNP/NT-proBNP.21 Another study looking at the prediction value of coronary computed tomographic angiography (CCTA) in addition to RCRI found that CCTA improved risk discrimination only for patients who had a postoperative cardiac event. For patients who did not have a postoperative cardiac event, CCTA inappropriately overestimated patients’ perioperative cardiac risk.22 The study did not compare CCTA to BNP/NT-proBNP. Studies on preoperative coronary revascularization prior to noncardiac surgery have shown conflicting results on preventing perioperative cardiac events.23,24 One hypothesis behind the limited utility of preoperative cardiac imaging for risk stratification is that coronary anatomy may not be the most dominant factor driving perioperative cardiac risk. In other words, an image may not be as informative on the heart’s health and physiology as a biological marker. This may explain why studies of routine preoperative BNP/NT-proBNP in patients with baseline risk factors have shown more compelling evidence for preoperative cardiac risk prediction than studies