The role of brain natriuretic peptides as amarker for diagnosing cardiac syncope: A narrative review

Cardiac disease is the second common cause of syncope in emergency departments. Patients with Cardiac syncope have a higher risk of mortality than those who have a non-cardiac problem. Brain natriuretic peptide (BNP) as a cardiac marker has not thoroughly been evaluated in patients with syncope. This article focuses on the studies that have assessed BNP and NT-pro-BNP in cardiac and non-cardiac syncope patients in emergency departments.


INTRODUCTION
Syncope is defined as a temporary loss of consciousness followed by spontaneous and complete recovery 1 . In general populations, syncope is a common problem with the lifetime prevalence of 42% 2 . It is estimated that 3% of referrals to emergency departments and 2% of inpatient admissions are due to syncope, and 6 out of 1000 people are affected by this problem every year 3,4 . Kapoor et al. published one of the first prospective syncope studies and showed that the risk of mortality due to syncope in a 12-month follow-up was 14% 5 . Serious underlying conditions such as dysrhythmia, structural heart disease, and significant hemorrhage can be the causes of syncope which ultimately lead to mortality and morbidity. The underlying conditions can be cardiac or vascular. The cardiac conditions are dysrhythmia and myocardial infarction (MI), and the vascular conditions are hemorrhage, aortic dissection, and pulmonary embolism 6,7 . The serum marker BNP which is increasingly established in emergency departments for the diagnosis of acute heart failure can reflect the presence of structural heart disease [8][9][10] . Many studies have stated that cardiac syncope is caused by reduced cardiac output that is associated with impaired hemodynamic in arrhythmia or structural cardiac disorders 11 . Therefore, brain natriuretic peptides are candidates for diagnosis of cardiac syncope. During the last decade, few studies were conducted to assess the role of BNP in isolating cardiac from non-cardiac syncope. This paper aimed to discuss the studies that evaluated the effect of brain natriuretic peptides on diagnosis and prediction of cardiac syncope in emergency departments.

SYNCOPE RISK STRATIFICATION IN EMERGENCY DEPARTMENTS
In risk stratification and diagnosis of syncope, we must consider three major issues addressed by Costantino et al. 12 : Differentiating patients with syncope from those with loss of consciousness of no syncopal source According to the European Society of Cardiology (ESC) guidelines, syncope is defined as a transient loss of consciousness (T-LoC) caused by transient cerebral hypo-perfusion characterized by loss of consciousness followed by spontaneous and complete recovery 13 . Therefore, syncope must be distinguished from T-LoC not induced by cerebral hypoperfusion Table 1.

Distinguishing patients with syncope from those who have fallen
Most of the time, distinguishing syncope from fall in clinical practice is impossible and exhausting. Taking a careful history from a witness plays a crucial role in facilitating the diagnosis during the early evaluation in the ED.
Determining how to manage patients presenting to the ED with near syncope or presyncope Management  Many studies performed in emergency departments exclude presyncope or near syncope because it is often assumed that these patients have a good prognosis. However, Grossman et al. compared the clinical outcomes of the patients with pre-syncope and the individuals with syncope, and no statistically significant difference was found between the two groups. They concluded that the prognosis of near syncope was similar to that of syncope.

SYNCOPE RULES
In emergency departments, many rules have been established to stratify the risk of a single patient presenting with syncope 14 . Examples of such rules are the San Francisco Syncope Rule (SFSR), Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL), Evaluation of Guidelines in Syncope Study (EGSYS), risk stratification of syncope in the emergency department (Rose), and Boston Syncope Rules. Among these rules, only SFRS had external validity in the systematic review by Saccilotto et al. 15 with the sensitivity of 87% (95%CI 79-93) and specificity of 52% (95% CI 43-62). One of these rules that considers the N-Terminal pro-brain natriuretic peptide (NT-proBNP) and BNP is Rose published in 2010 and derived and validated in a single ED center in Edinburgh 16

DIAGNOSTIC VALUE OF BNP IN CHILDREN WITH SYNCOPE
Syncope is a common problem in children and adolescents. A prevalence rate of 15% has been estimated for the syncopal episode in children under the age of 18 [21][22][23] . Syncope in children and adolescents can be caused by underlying conditions. The most common type of syncope in children and adolescent is autonomic-mediated reflex syncope (AMS), resulted from the syncope caused by cardiac diseases 17,24,25 . About 1-3% of children's and adolescents' admission in ED is associated with syncope (23)(24). In our electronic search, we identified two studies on BNP value and syncope in children and adolescents. In a study by Wójtowicz J et al. 24 who evaluated Natriuretic peptides in the children and adolescents with syncope, there was no significant difference in terms of BNP level between the syncope and control groups at all. Their study started with 88 and 25 participants in the syncope and control groups, respectively. The concentration of NT-proBNP in the syncope group was 24.5 pg/mL, and that of NT-proBNP was 4.8pg/mL. In the control group, NT-proBNP and ANP concentrations were 25 pg/mL and 3 pg/mL, respectively, which had no significant difference with the syncope group. Also, the children who were hospitalized due to syncope showed a significant difference in beats per min and a maximum heart rate during the 24-h electrocardiographic Holter monitoring. In another study, Zhang Q et al. 25 evaluated "Diagnostic value of serum brain natriuretic peptide in syncope in children and adolescents. " The study concluded that Serum BNP was helpful in differentiating cardiac syncope from non-cardiac syncope in children and adolescents. Sixty-two children and adolescents admitted in ED for syncope were evaluated, among whom 23 participants had cardiac syncope, and 39 had non-cardiac syncope. Regarding BNP levels, there was a significant difference between cardiac syncope (958.78 ± 2443.41 pg/mL) and noncardiac syncope (31.05 ± 22.64pg/mL) groups (Pvalue <0.05). Furthermore, a significant difference

DIAGNOSTIC VALUE OF BNP IN ADULTS WITH SYNCOPE
In the electronic search strategy, six studies were identified in which the inclusion criterion was adult syncope. Summaries of these studies are shown in Table 2. A significant difference was found between the mean ages in cardiac syncope compared to noncardiac syncope in four studies. In the cardiac syncope groups, age was higher than in the non-cardiac syncope ones, and the cause of this relationship was unclear. The results of these studies showed that measuring the BNP level in EDs was very helpful for diagnosis of the individuals with cardiac syncope, and decreased the chance of mortality due to cardiac syncope by using guidelines or rules. Tanimoto K et al. 17 studied BNP for separating cardiac and non-cardiac syncope, and considered the cut-off value of 40 pg/ml for isolating cardiac and non-cardiac syncope with 82% sensitivity and 92% specificity for identification of cardiac syncope. The authors of this study concluded that a significant relationship was found in terms of BNP level between the cardiac group (118±42 pg/ml) and those in the other three groups (Reflex-mediated, Neurologic, and Unknown). Pfister et al. 8 showed that the assessment of NT-pro-BNP was helpful in differentiating cardiac from non-cardiac syncope. A significant difference was observed in BNP level for cardiac group compared to the non-cardiac one (514 pg/ml vs. 182 pg/ml, P-value <0.05). The authors of this study also concluded that the NT-pro-BNP had a high sensitivity and a high negative predictive value for the cardiac cause in patients with syncope and was a better predictor than clinical and ECG features.

CONCLUSION
We concluded that a biochemical marker such as BNP and other forms of this marker was very helpful in separating and diagnosing cardiac syncope patients and predicting their mortality. This marker, as well as other ones, seem to be very helpful in emergency departments. The accuracy and precision of diagnosing and predicting prognosis of cardiac syncope with Rules were increased. There are few studies on syncope in children, and more studies need to be conducted to clarify the causal relationship.

RECOMMENDATIONS AND FUTURE STUDIES
According to some of the recommendations in previous studies, more research is needed to be conducted to clarify this relationship and the variables that might play the role of confounders in a causal inference.
More studies are required on children because there is some controversy in this relationship. And finally, we suggest to study syncope patients with large sample sizes and randomized control trial studies to ensure that this marker is helpful in recognizing and predicting the prognosis of the disease.