Arq Bras Cardiol Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC WZs3vr5VM4zswGXwNtVkYrd S0066-782X2015000100004 S0066-782X2014005040175 00004 10.5935/abc.20140175 Original Articles BNP was Associated with Ischemic Myocardial Scintigraphy and Death in Patients at Chest Pain Unit Azevedo Jader Cunha de 1 2 3 Reis Bruno Cezario Costa 3 Barreto Nathalia Monerat P.B. 3 F. Diogenes S. Junior 1 Prezotti Lais S. 1 Procaci Victor Rebelo 3 Octaviano Vivian Werneck 3 Volschan Andre 2 Mesquita Evandro Tinoco 1 2 Mesquita Claudio Tinoco 1 2 Universidade Federal Fluminense Niterói Brazil Universidade Federal Fluminense, Niterói Hospital Pró-Cardíaco Brazil Hospital Pró-Cardíaco Centro Universitário de Volta Redonda Rio de Janeiro RJ Brazil Centro Universitário de Volta Redonda, Rio de Janeiro , RJ - Brazil Mailing Address: Jader Cunha de Azevedo, Hospital Pró-Cardiaco - Serviço de Medicina Nuclear, Rua General Polidoro, 192 - Botafogo, Rio de Janeiro - RJ, Postal Code 22280-000. E-mail: jadercazevedo@gmail.com; jadercazevedo@cardiol.br

Author contributions

Conception and design of the research: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Acquisition of data: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Analysis and interpretation of the data: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Statistical analysis: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Obtaining Financing: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Writing of the manuscript: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Critical revision of the manuscript for intellectual content: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 01 2015 18 11 2014 104 1 16 23 31 01 2014 18 06 2014 22 07 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Background:

Recent studies have suggested that B-type Natriuretic Peptide (BNP) is an important predictor of ischemia and death in patients with suspected acute coronary syndrome. Increased levels of BNP are seen after episodes of myocardial ischemia and may be related to future adverse events.

 Objectives:

To determine the prognostic value of BNP for major cardiac events and to evaluate its association with ischemic myocardial perfusion scintigraphy (MPS).

 Methods:

This study included retrospectively 125 patients admitted to the chest pain unit between 2002 and 2006, who had their BNP levels measured on admission and underwent CPM for risk stratification. BNP values were compared with the results of the MPS. The chi-square test was used for qualitative variables and the Student t test, for quantitative variables. Survival curves were adjusted using the Kaplan-Meier method and analyzed by using Cox regression. The significance level was 5%.

 Results:

The mean age was 63.9 ± 13.8 years, and the male sex represented 51.2% of the sample. Ischemia was found in 44% of the MPS. The mean BNP level was higher in patients with ischemia compared to patients with non-ischemic MPS (188.3 ± 208.7 versus 131.8 ± 88.6; p = 0.003). A BNP level greater than 80 pg/mL was the strongest predictor of ischemia on MPS (sensitivity = 60%, specificity = 70%, accuracy = 66%, PPV = 61%, NPV = 70%), and could predict medium-term mortality (RR = 7.29, 95% CI: 0.90-58.6; p = 0.045) independently of the presence of ischemia.

 Conclusions:

BNP levels are associated with ischemic MPS findings and adverse prognosis in patients presenting with acute chest pain to the emergency room, thus, providing important prognostic information for an unfavorable clinical outcome.

 Natriuretic Peptide Brain Heart Failure Myocardial Perfusion Imaging Myocardial Ischemia Introduction

Currently, several biomarkers are important tools for diagnosis, risk stratification and therapeutic decision making in cardiovascular diseases 1-4. Brain Natriuretic Peptide (BNP), mainly synthesized by ventricular myocytes from a precursor, pre-pro BNP, is released by stimulating cardiac myocyte stretch, caused by pressure or volume overload in the heart5-7. The most studied use of BNP to date is in the diagnosis, prognosis and management of patients with heart failure (HF)2,7-15. Another emerging use of BNP is in the diagnosis and prognosis of patients with acute coronary syndrome (ACS). There is evidence that there is a direct release of BNP in response to ischemia, even in the absence of myocardial necrosis16-22. Myocardial perfusion scintigraphy (MPS) has been widely used as an important tool in decision making in patients with acute chest pain 23-24. Its value in the diagnosis of acute myocardial infarction (AMI) and in the prognosis of patients admitted with ACS has been well established 25-27. Our group has recently demonstrated that ischemia detected by MPS was the major independent factor in predicting adverse events for patients admitted with acute chest pain to the emergency room 24. Considering that the availability of complex imaging procedures in the emergency room is limited to reference centers and that the prevalence of ACS is high, this study aims to evaluate if the use of BNP at the chest pain unit (CPU) can determine adverse cardiac events in the medium term, as well as to evaluate its association with the MPS findings.

 Methods Participants

We conducted a retrospective observational study and selected consecutive patients admitted to the CPU of a tertiary hospital from December 2002 to April 2006. Participants in this study were recruited from a consecutive cohort of patients admitted to the CPU complaining of "chest pain". This study was approved by the Research Ethics Committee of the Hospital Pró-Cardíaco under registration No. 137/2005. Signed Informed Consent was not required. This study had no external funding sources.

 Blood analysis

Blood was collected on admission to the CPU, and the blood samples were centrifuged at 4000 rpm. BNP was measured in all samples by use of sandwich enzyme immunoassay technique (Alere Triage® BNP Test) with the lowest sensitivity of 5 pg/mL. The intra- and interassay coefficient of variation was lower than 10% for all assays.

 Myocardial Perfusion Scintigraphy

All patients underwent clinical investigation that consisted of performing ECG and MPS with physical or pharmacological stress (dipyridamole or adenosine or dobutamine), as well as measuring myocardial necrosis markers (troponin-I and CK-MB mass) and BNP. They were evaluated according to the institutional protocol of chest pain 26. After the exclusion of AMI or high-risk unstable angina (UA), the patients underwent rest and stress MPS for coronary risk stratification. Those who did not undergo the two phases of the test and those with incomplete medical records were excluded from the study.

All the tests were carried out in a dual head gamma camera (Ecam-Duet Siemens, Milpitas, USA), with a low-energy and high resolution collimator with tomographic image acquisition (SPECT - Single Photon Emission Computed Tomography) gated with ECG, with 64 projections and a 64 x 64 matrix. After their acquisition, the images were reconstructed through back projection with a Butterworth filter, and processed using e-Soft (Emory Cardiac Toolbox™, an image processing software package. The analysis of global and segmental contractility and of ejection fraction was accomplished by using gated SPECT. The unit used the 17-segment myocardial segmentation model 27. The tests were evaluated by two experienced physicians, certified in Nuclear Medicine and Cardiology.

Clinical data and the results of laboratory tests relative to the studied population were obtained from the patients' hospital files, which were considered the main data source. The following clinical variables were analyzed: sex, age, systemic arterial hypertension, dyslipidemia, smoking, sedentary lifestyle, diabetes mellitus, family history of coronary artery disease, obesity, history of AMI, and previous surgical myocardial revascularization (CABG) or percutaneous transluminal coronary angioplasty (PTCA).

The scintigraphic variables were: the type of stress used, the number of segments showing reversible perfusion defects (ischemia) and fixed defects (fibrosis) on qualitative analysis, and quantification of these defects by using software (Cedars Sinai and Emory Cardiac Toolbox); analysis of global and segmental contractility and ejection fraction.

 Follow-up

We collected information on adverse events that took place after patients' discharge from hospital. The interventions (PTCA, CABG) performed during hospitalization were not considered as adverse events, but as a result of treatment. Follow-up was conducted via telephone with information obtained from patients, relatives, families or doctors, or via hospital records, when available. We collected information about events occurring after hospital discharge, the primary outcome being death, and the secondary outcome, a combination of events, death and AMI. Acute myocardial infarction was defined as a new episode of chest pain lasting more than 20 minutes and requiring hospitalization, which was confirmed by the elevation of myocardial necrosis markers (creatine phosphokinase fraction MB [CK-MB] or Troponin I) or the appearance of Q waves on ECG and the need for reperfusion therapy with thrombolysis or emergency PTCA.

 Statistical analysis

The chi-square test or Fisher's exact test was used for categorical variables. To assess the continuous variables between the two groups, Student ttest was used for independent samples. Multivariate analysis, to identify independent factors that simultaneously influence or explain the occurrence of events and to assess the simultaneous influence of clinical variables on events, was carried out using logistic regression. Stepwise regression with a significance level of 5% was used to select the factors. The event-free survival rate (neither primary nor secondary outcomes) was adjusted by the Kaplan-Meier method and Cox regression for analysis. Log-rank test was used to verify if there was significant difference in the event-free survival curve for primary and combined events stratified according to the MPS results. The difference was considered significant for a p value lower than 0.05, and highly significant for a p value lower than 0.01. The SPSS software (SPSS version 19.0, SPSS Inc., Chicago, IL, USA) was used for statistical analysis.

 Results

This study assessed 64 men and 61 women, whose mean age was 63.9 ± 13.8 years. Tables 1 and 2 show the reported symptoms on admission and the clinical characteristics of the population, respectively. Based on the MPS findings, 55 (44%) patients had ischemia, 34 of whom (61.8%) were men. Statistically significant difference was observed regarding sex (p = 0.035), smoking history (p = 0.003), history of diabetes (p = 0,04) and history of coronary heart disease (p <0.001)]. These and other clinical characteristics are shown in Table 3. The absolute value of BNP was higher in patients with ischemia than in those with normal MPS (188.3 ± 208.7 versus 131.8 ± 88.6; p = 0.003), as shown in Figure 1.

Symptoms
  n %
Chest pain A 06 4.8
Chest pain B 77 61.6
Chest pain C 24 19.2
Chest pain D 0 0
Dyspnea 11 8.8
Palpitation 04 3.2
Dizziness 05 4.0
Syncope 01 0.8
Baseline characteristics
  n %
Hypertension 92 73.6
Diabetes 22 17.6
Dyslipidemia 70 56.0
Sedentary lifestyle 61 48.8
Obesity 24 19.2
Smoking 38 30.4
Menopause 25 20.0
Coronary disease 70 56.0
Clinical characteristics correlated with ischemia
  Ischemia  
    Yes     No  
  N   % N   % p value
Male 34   53.1 30   46.9 0.035
Hypertension 43   46.7 49   53.3 0.300
Dyspnea 05   45.5 06   54.5 0.900
Diabetes 14   63.6 08   36.4 0.041
Coronary disease 41   58.6 29   41.4 < 0.001
Obesity 11   45.8 13   54.2 0.800
Smoking 24   63.1 14   36.9 0.003
Dyslipidemia 33   47.1 37   52.9 0.420
Menopause 06   27.3 16   72.7 0.080
Sedentary lifestyle 25   41 36   59 0.500
Box plot showing dispersion of BNP levels according to the presence (1) or absence (0) of ischemia.

The mean ejection fraction on gated SPECT was 62%±19%, and an ejection fraction lower than 45% correlated with BNP levels greater than 80 pg/mL (p= 0.002) and with ischemia on MPS (31% with ischemia had an ejection fraction lower than 45%, p=0.000).

Multivariate analysis showed that BNP greater than 80 pg/mL is a powerful independent marker for the diagnosis of ischemia on MPS (sensitivity = 60%, specificity = 70%, accuracy = 66%, PPV = 61%, NPV = 70%). An ejection fraction lower than 45% on gated SPECT correlated with neither ischemia on MPS (p=0.12) nor death on multivariate analysis (p=0.9).

The prognosis analysis by use of logistic regression and survival curve showed that the presence of BNP greater than 80 pg/mL could predict medium-term death (RR = 7.29, 95% CI = 0.90 to 58.6; p = 0.045) regardless of the presence of ischemia. The follow-up period was 700.5 ± 326.6 days. The combination of ischemia and high BNP did not worsen the mid-term prognosis (Figures 2, 3 and 4).

Survival curve according to BNP levels and presence of ischemia. Blue line represents patients with no ischemia on MPS and BNP levels under 80 pg/mL. Green line represents patients with no ischemia and BNP above 80 pg/mL. Yellow line represents patients with ischemia on MPS and BNP levels under 80 pg/mL, and purple line represents patients with both ischemia on MPS and BNP levels above 80 pg/mL Survival curve according to BNP level. Blue line represents patients with BNP levels above 80 pg/mL and green line represents patients with BNP levels under 80 pg/mL. Survival curve relative to presence of ischemia (green line) or absence of ischemia (blue line). Discussion

The past 30 years have seen a continuous search for new biomarkers for diagnosis, prognosis, risk stratification and therapeutic decision making in patients with chest pain in the emergency room. Epidemiology also shows importance in the search for new techniques that accelerate the diagnosis and avoid complications in patients at risk of cardiovascular disease, which currently occupies the first place in the morbidity and mortality rates worldwide 28-30. A wide range of biomarkers has been evaluated in the context of cardiovascular diseases, such as adrenomedullin, natriuretic peptides (NT-pro ANP and NT-proBNP), co-pectin, choline, C-reactive protein (CRP), the ligand CD40 (CD40L), cystatin C (Cys C), fibrinogen, and, more recently, intermedin 30,31. Despite the existence of several markers, BNP has proved to be one of the best diagnostic tools in the emergency room, not only as a screening test for patients with complaints of dyspnea, but also to assist in the diagnosis and prognosis of patients with chest pain 12-14. Dao et al.32 have demonstrated that BNP has a well-established role in the evaluation of patients with dyspnea of unknown etiology in the emergency room. In their study, BNP was measured in 250 patients who presented with dyspnea as a chief complaint in the emergency department, and the results indicated a significant discrepancy between the BNP values in patients with and without a HF diagnosis. It is also important to highlight that BNP values ​​of 80 pg/ml were highly sensitive and specific for the diagnosis of HF 32.

Another applicability of BNP may be in the evaluation of ACS. Some studies have also shown that after AMI, a high BNP level is associated with more extensive infarctions, greater chance of ventricular remodeling, lower ejection fraction and a higher risk of HF and death 33-36. Foote et al. 37 have suggested that exercise-induced ischemia and the measurement of plasma NT-pro-BNP and BNP levels before and immediately after symptom-limited exercise can distinguish between patients with and without ischemia, whereas ischemia is defined as a reversible defect on scintigraphy, with a high degree of accuracy. The hypothesis is that exercise-induced ischemia, can indirectly cause abnormalities of regional wall motion, resulting in increases in detectable BNP levels. Patients with induced ischemia compared with those without ischemia have higher elevations of NT-proBNP and BNP levels, corroborating that hypothesis. Thus, an exercise-induced increase in BNP can be considered a marker of induced ischemia, and this finding is more accurate in detecting ischemia than ST-segment depression during exercise testing 37. In addition, other studies have shown the prognostic value of BNP. Harrison et al. 38 have investigated whether BNP levels of patients arriving at the emergency department with acute dyspnea could be a predictor of future cardiac events. Those authors have concluded that in this population of patients with acute dyspnea, BNP values could be highly predictive of cardiac events at six months. Sabatine et al.16 have also demonstrated the prognostic value of BNP in the context of ACS and observed that a high initial level of this peptide correlates with the risk of death, HF or myocardial infarction at 30 days and 10 months. In our study we found that BNP greater than 80 pg/mL was the most powerful independent marker for the diagnosis of ischemia on MPS. Furthermore, the presence of BNP levels greater than 80 pg/mL had a high predictive power for death, being associated with a 7-fold increase in the relative risk as compared with BNP levels below that value. Therefore our study, in agreement with previously published data, suggests that the implementation of BNP evaluation may be useful for risk stratification of patients with chest pain and suspected ACS without ST elevation and negative troponin.39 An additional issue to be discussed is that, although our work demonstrated that elevated BNP levels correlated with poor prognosis, these levels have no additional value to predict adverse events in patients with ischemia. In a recent study, Nadir et al. 40 have demonstrated that BNP can identify ischemia better than troponin does, but have not demonstrated the values that are predictors of myocardial ischemia, which further enhances our study.

 Conclusions

The present study demonstrated that in patients admitted to the emergency department complaining of chest pain, who subsequently showed ischemia on MPS, had higher BNP levels than those with normal MPS, showing the close relationship of BNP as an independent marker of ischemia. Furthermore, we have demonstrated through analysis of prognosis that BNP levels greater than 80 pg/mL were able to predict death, being a useful marker in that population.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the dissertation of Jader Cunha de Azevedo by Programa de Pós-Graduação em Ciências Cardiovasculares - Universidade Federal Fluminense.

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Qina YW Tengb X Hea JQ Dua J Tanga CS Qia YF Increased plasma levels of intermedin and brain natriuretic peptide associated with severity of coronary stenosis in acutecoronary syndrome Peptides 2013 42 84 88 Dao Q, Krishnaswamy P, Kazanegra R, Harrison A, Amirnovin R, Lenert L, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol. 2001;37(2):379-85. Dao Q Krishnaswamy P Kazanegra R Harrison A Amirnovin R Lenert L et al Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting J Am Coll Cardiol 2001 37 2 379 385 Arakawa N, Nakamura M, Aoki H, Hiramori K. Relationship between plasma level of brain natriuretic peptide and myocardial infarct size. Cardiology. 1994;85(5):334-40. Arakawa N Nakamura M Aoki H Hiramori K Relationship between plasma level of brain natriuretic peptide and myocardial infarct size Cardiology 1994 85 5 334 340 Nagaya N, Nishikimi T, Goto Y, Miyao Y, Kobayashi Y, Morii I, et al. Plasma brain natriuretic peptide is a biochemical marker for the prediction of progressive ventricular remodeling after acute myocardial infarction. Am Heart J. 1998;135(1):21-8. Nagaya N Nishikimi T Goto Y Miyao Y Kobayashi Y Morii I et al Plasma brain natriuretic peptide is a biochemical marker for the prediction of progressive ventricular remodeling after acute myocardial infarction Am Heart J 1998 135 1 21 28 Richards AM, Nicholls MG, Yandle TG, Ikram H, Espiner EA, Turner JG, et al. Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine Research Group. Heart. 1999;81(2):114-20. Richards AM Nicholls MG Yandle TG Ikram H Espiner EA Turner JG et al Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. The Christchurch Cardioendocrine Research Group Heart 1999 81 2 114 120 Richards AM, Nicholls MG, Yandle TG, Frampton C, Espiner EA, Turner JG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998;97(19):1921-9. Richards AM Nicholls MG Yandle TG Frampton C Espiner EA Turner JG et al Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction Circulation 1998 97 19 1921 1929 Foote RS, Pearlman JD, Siegel AH, Yeo KT. Detection of exercise-induced ischemia by changes in B-type natriuretic peptides. J Am Coll Cardiol. 2004;44(10):1980-7. Foote RS Pearlman JD Siegel AH Yeo KT Detection of exercise-induced ischemia by changes in B-type natriuretic peptides J Am Coll Cardiol 2004 44 10 1980 1987 Harrison A, Morrison LK, Krishnaswamy P, Kazanegra R, Clopton P, Dao Q, et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med. 2002;39(2):131-8. Harrison A Morrison LK Krishnaswamy P Kazanegra R Clopton P Dao Q et al B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea Ann Emerg Med 2002 39 2 131 138 Weber M, Bazzino O, Estrada JL, Fuselli JJ, Botto F, Arenaza DP, et al. N-terminal B-type natriuretic peptide assessment provides incremental prognostic information in patients with acute coronary syndromes and normal troponin T values upon admission. J Am Coll Cardiol. 2008;51(12):1188-95. Weber M Bazzino O Estrada JL Fuselli JJ Botto F Arenaza DP et al N-terminal B-type natriuretic peptide assessment provides incremental prognostic information in patients with acute coronary syndromes and normal troponin T values upon admission J Am Coll Cardiol 2008 51 12 1188 1195 Nadir MA, Dow E, Davidson J, Kennedy N, Lang CC, Struthers AD. Myocardial ischaemia is associated with an elevated brain natriuretic pepide level even in the presence of left ventricular systolic dysfunction. Eur J Heart Fail. 2014;16(1):56-67. Nadir MA Dow E Davidson J Kennedy N Lang CC Struthers AD Myocardial ischaemia is associated with an elevated brain natriuretic pepide level even in the presence of left ventricular systolic dysfunction Eur J Heart Fail 2014 16 1 56 67 Associação de BNP com Isquemia na Cintilografia Miocárdica e Morte em Pacientes da Unidade de Dor Torácica Azevedo Jader Cunha de 1 2 3 Reis Bruno Cezario Costa 3 Barreto Nathalia Monerat P.B. 3 F. Diogenes S. Junior 1 Prezotti Lais S. 1 Procaci Victor Rebelo 3 Octaviano Vivian Werneck 3 Volschan Andre 2 Mesquita Evandro Tinoco 1 2 Mesquita Claudio Tinoco 1 2 Universidade Federal Fluminense Niterói Universidade Federal Fluminense, Niterói Hospital Pró-Cardíaco Hospital Pró-Cardíaco Centro Universitário de Volta Redonda Rio de Janeiro RJ Brazil Centro Universitário de Volta Redonda, Rio de Janeiro , RJ - Brazil Correspondência: Jader Cunha de Azevedo, Hospital Pró-Cardiaco - Serviço de Medicina Nuclear. Rua General Polidoro, 192 - Botafogo, Rio de Janeiro - RJ, CEP 22280-000. E-mail: jadercazevedo@gmail.com; jadercazevedo@cardiol.br

Contribuição dos autores

Concepção e desenho da pesquisa: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Obtenção de dados: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Análise e interpretação dos dados: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Análise estatística: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Obtenção de Financiamento: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Redação do manuscrito: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Azevedo JC, Reis BCC, Barreto NMPB, F. Junior DS, Prezotti LS, Procaci VR, Octaviano VW, Volschan A, Mesquita ET, Mesquita CT.

Potencial Conflito de Interesses

Declaro não haver conflito de interesses pertinentes.

 Fundamentos:

Recentes estudos sugeriram que o peptídeo natriurético do tipo B (BNP) seja um importante fator preditivo de isquemia e morte em pacientes com suspeita de síndrome coronariana aguda. Níveis elevados de BNP são observados após episódios de isquemia miocárdica e podem estar relacionados a futuros eventos adversos.

 Objetivos:

Determinar o valor prognóstico do BNP para eventos cardíacos maiores e avaliar sua associação com cintilografia de perfusão miocárdica (CPM) isquêmica.

 Métodos:

Este estudo incluiu retrospectivamente 125 pacientes admitidos na unidade de dor torácica entre 2002 e 2006, quando seus níveis de BNP foram medidos, tendo sido submetidos a CPM para estratificação de risco. Os níveis de BNP foram comparados com os resultados da CPM. O teste do qui-quadrado foi usado para avaliar as variáveis qualitativas e o teste t de Student, para as quantitativas. Curvas de sobrevida foram ajustadas usando-se o método de Kaplan-Meier e analisadas com regressão de Cox. Adotou-se o nível de significância de 5%.

 Resultados:

A idade média foi de 63,9 ± 13,8 anos, e o sexo masculino correspondeu a 51,2% da amostra. Isquemia foi identificada em 44% das CPM. O BNP médio foi maior em pacientes com isquemia do que naqueles sem isquemia na CPM (188,3 ± 208,7 versus 131,8 ± 88,6; p = 0,003). Um nível de BNP acima de 80 pg/ml mostrou-se o mais forte fator preditivo de isquemia na CPM (sensibilidade = 60%, especificidade = 70%, acurácia = 66%, VPP = 61%, VPN = 70%), tendo sido capaz de predizer morte em médio prazo (RR = 7,29, IC 95%: 0,90-58,6; p = 0,045) independentemente da presença de isquemia.

 Conclusões:

Os níveis de BNP estão associados com achados isquêmicos na CPM e prognóstico adverso em pacientes que se apresentam no setor de emergência queixando-se de dor torácica aguda, fornecendo, portanto, importante informação prognóstica para um desfecho clínico desfavorável.

 Peptídeo Natriurético Encefálico Insuficiência Cardíaca Imagem de Perfusão Miocárdica Isquemia Miocárdica Introdução

Atualmente, vários biomarcadores são importantes ferramentas para o diagnóstico, a estratificação de risco e a tomada de decisão terapêutica em doenças cardiovasculares1-4. O peptídeo natriurético do tipo B (BNP), sintetizado principalmente pelos miócitos ventriculares a partir de um precursor, o pré-pro BNP, é liberado mediante o estímulo de estiramento de miócitos cardíacos, causado por sobrecarga de pressão ou volume no coração5-7. Até o momento, o uso do BNP foi mais estudado para o diagnóstico, prognóstico e tratamento de pacientes com insuficiência cardíaca (IC)2,7-15. Outro uso emergente para o BNP é o diagnóstico e o prognóstico de pacientes com síndrome coronariana aguda (SCA). Há evidência de que existe liberação direta de BNP em resposta a isquemia, mesmo na ausência de necrose miocárdica16-22. A cintilografia de perfusão miocárdica (CPM) tem sido amplamente usada como importante ferramenta na tomada de decisão para o manejo de pacientes com dor torácica aguda23,24. Seu valor no diagnóstico do infarto agudo do miocárdio (IAM) e no prognóstico de pacientes internados com SCA já está bem estabelecido25-27. Em trabalho recente, nosso grupo demonstrou que a isquemia detectada por CPM foi o principal fator independente para a predição de eventos adversos em pacientes admitidos com dor torácica aguda no setor de emergência24. Considerando que a disponibilidade de procedimentos de imagem complexos no setor de emergência acha-se limitada a centros de referência e que a prevalência de SCA é alta, este estudo visa a avaliar se o uso de BNP na unidade de dor torácica (UDT) pode determinar eventos cardíacos adversos a médio prazo, além de avaliar sua associação com os resultados da CPM.

 Metodos Participantes

Este estudo retrospectivo e observacional selecionou pacientes consecutivos admitidos na UDT de um hospital terciário de dezembro de 2002 a abril de 2006. Os participantes foram recrutados de uma coorte consecutiva de pacientes admitidos na UDT queixando-se de "dor torácica". Este estudo foi aprovado pelo Comitê de Ética em Pesquisa do Hospital Pró-Cardíaco (registro No. 137/2005). Não foi necessário assinar termo de consentimento livre e informado. Este estudo não teve fontes externas de financiamento.

 Análise de sangue

Amostras de sangue foram coletadas na admissão na UDT, sendo depois centrifugadas a 4000 rpm. A dosagem de BNP foi realizada em todas as amostras pela técnica de imunoensaio tipo sanduíche (Alere Triage® BNP Test), com sensibilidade mínima de 5 pg/ml. O coeficiente de variação intra- e interensaio foi menor do que 10% para todos os ensaios.

 Cintilografia de perfusão miocárdica

Todos os pacientes foram submetidos a investigação clínica que consistiu na realização de ECG e CPM com estresse físico ou farmacológico (dipiridamol, adenosina ou dobutamina), assim como a dosagem de marcadores de necrose miocárdica (troponina-I e CK-MB massa) e de BNP. Foram avaliados de acordo com o protocolo institucional de dor torácica26. Após exclusão de IAM ou angina instável (AI) de alto risco, os pacientes foram submetidos a CPM de repouso e estresse para estratificação de risco coronário. Os pacientes não submetidos às duas fases do exame e aqueles com dados incompletos no prontuário médico foram excluídos do estudo.

Todos os exames foram realizados em gama câmara de dois detectores (Ecam-Duet - Siemens, Milpitas, EUA), com colimador de baixa energia e alta resolução e aquisição de imagem tomográfica (SPECT - Single Photon Emission Computed Tomography) com sincronização com ECG, com 64 projeções e matriz 64 x 64. Após a aquisição, as imagens foram reconstruídas através de retroprojeção filtrada com filtro Butterworth, e processadas usando-se e-Soft (Emory Cardiac Toolbox(tm)), um programa de processamento de imagem. A contratilidade global e segmentar e a fração de ejeção foram analisadas usando-se gated SPECT. Utilizou-se o modelo de segmentação miocárdica em 17 segmentos27. Os exames foram avaliados por dois médicos experientes, com certificação em Medicina Nuclear e Cardiologia.

Os dados clínicos e os resultados dos exames laboratoriais da população estudada foram obtidos dos prontuários dos pacientes, que foram considerados a principal fonte de informação. As seguintes variáveis clínicas foram analisadas: sexo, idade, hipertensão arterial sistêmica, dislipidemia, tabagismo, estilo de vida sedentário, diabetes mellitus, história familiar de doença arterial coronária, obesidade, história de IAM, e prévia revascularização miocárdica cirúrgica (RMC) ou angioplastia coronária transluminal percutânea (PTCA).

As seguintes variáveis cintilográficas foram analisadas: tipo de estresse usado, número de segmentos mostrando defeitos de perfusão reversíveis (isquemia) e fixos (fibrose) na análise qualitativa, e quantificação desses defeitos usando-se o programa de processamento de imagem (Cedars Sinai e Emory Cardiac Toolbox™; análise da contratilidade global e segmentar e da fração de ejeção.

 Seguimento

Coletamos informação sobre eventos adversos ocorridos após a alta hospitalar. As intervenções (PTCA, RMC) realizadas durante a hospitalização não foram consideradas eventos adversos, mas um resultado do tratamento. O seguimento foi conduzido por telefone com informação obtida dos pacientes, parentes, famílias ou médicos, ou através dos prontuários médicos, quando disponíveis. Os eventos ocorridos após a alta hospitalar considerados foram: desfecho primário, morte; e desfecho secundário, combinação de eventos, morte e IAM. O IAM foi definido como um novo episódio de dor torácica com mais de 20 minutos de duração, necessitando de hospitalização, e que foi confirmado pela elevação dos marcadores de necrose miocárdica (creatina fosfoquinase fração MB [CK-MB] ou troponina I) ou aparecimento de ondas Q no ECG e a necessidade de terapia de reperfusão com trombólise ou PTCA de urgência.

 Análise estatística

O teste do qui-quadrado ou o teste exato de Fisher foi usado para as variáveis categóricas. Para avaliar as variáveis contínuas entre os dois grupos, o teste t de Student foi usado para amostras independentes. Realizou-se análise multivariada com regressão logística para identificar fatores independentes que influenciam simultaneamente ou explicam a ocorrência de eventos e para avaliar a influência simultânea de variáveis clínicas nos eventos. Regressão stepwise com nível de significância de 5% foi usada para selecionar os fatores. A taxa de sobrevida sem eventos (nem desfechos primários nem secundários) foi ajustada pelo método de Kaplan-Meier e regressão de Cox para análise. Usou-se o teste log-rank para verificar se havia uma significativa diferença na curva de sobrevida sem eventos para eventos primários e combinados estratificados de acordo com os resultados da CPM. A diferença foi considerada significativa para um valor de p menor do que 0,05, e altamente significativa para um valor de p menor do que 0,01. O programa SPSS (SPSS versão 19.0, SPSS Inc., Chicago, IL, EUA) foi usado para análise estatística.

 Resultados

Este estudo avaliou 64 homens e 61 mulheres, cuja idade média foi de 63,9 ± 13,8 anos. As Tabelas 1 e 2 mostram os sintomas relatados na admissão e as características clínicas da população, respectivamente. De acordo com os resultados da CPM, 55 (44%) pacientes apresentaram isquemia, 34 dos quais (61,8%) eram homens. Diferença estatisticamente significativa foi observada com relação a sexo (p = 0,035), história de tabagismo (p = 0,003), de diabetes (p = 0,04) e de doença arterial coronária (p <0,001)]. A Tabela 3 mostra essas e outras características clínicas. O valor absoluto do BNP foi maior em pacientes com isquemia do que naqueles com CPM normal (188,3 ± 208,7 versus 131,8 ± 88,6; p = 0,003) (Figura 1).

Sintomas
  n %
Dor torácica A 06 4,8
Dor torácica B 77 61,6
Dor torácica C 24 19,2
Dor torácica D 0 0
Dispneia 11 8,8
Palpitação 04 3,2
Vertigem 05 4,0
Síncope 01 0,8
Características basais
  n %
Hipertensão 92 73,6
Diabetes 22 17,6
Dislipidemia 70 56,0
Sedentarismo 61 48,8
Obesidade 24 19,2
Tabagismo 38 30,4
Menopausa 25 20,0
Doença coronária 70 56,0
Características clínicas relacionadas com isquemia
  Isquemia  
Sim Não
N % N % valor de P
Masculino 34 53,1 30 46,9 0,035
Hipertensão 43 46,7 49 53,3 0,300
Dispneia 05 45,5 06 54,5 0,900
Diabetes 14 63,6 08 36,4 0,041
Doença coronária 41 58,6 29 41,4 < 0,001
Obesidade 11 45,8 13 54,2 0,800
Tabagismo 24 63,1 14 36,9 0,003
Dislipidemia 33 47,1 37 52,9 0,420
Menopausa 06 27,3 16 72,7 0,080
Sedentarismo 25 41 36 59 0,500
Box plot mostrando dispersão dos níveis de BNP de acordo com a presença (1) ou ausência (0) de isquemia.

A fração de ejeção média no gated SPECT foi 62%±19%; uma fração de ejeção menor do que 45% correlacionou-se com níveis de BNP maiores do que 80 pg/ml (p= 0,002) e com isquemia na CPM (31% daqueles com isquemia tinham fração de ejeção menor do que 45%; p=0,000).

A análise multivariada mostrou que um BNP maior do que 80 pg/ml é um forte marcador independente para o diagnóstico de isquemia na CPM (sensibilidade = 60%, especificidade = 70%, acurácia = 66%, VPP = 61%, VPN = 70%). A fração de ejeção menor do que 45% no gated SPECT não se correlacionou com isquemia na CPM (p=0,12), nem com morte na análise multivariada (p=0,9).

A análise de prognóstico por regressão logística e curva de sobrevida mostrou que um nível de BNP maior do que 80 pg/ml pôde predizer a ocorrência de morte a médio prazo (RR = 7,29, IC 95%: 0,90-58,6; p = 0,045) independentemente da presença de isquemia. O seguimento durou 700,5 ± 326,6 dias. A combinação de isquemia e BNP alto não piorou o prognóstico de médio prazo (Figuras 2, 3 e 4).

Curva de sobrevida de acordo com os níveis de BNP e a presença de isquemia. A linha azul representa pacientes sem isquemia na CPM e níveis de BNP abaixo de 80 pg/ml. A linha verde representa pacientes sem isquemia e níveis de BNP acima de 80 pg/ml. A linha amarela representa pacientes com isquemia na CPM e níveis de BNP abaixo de 80 pg/ml, e a linha roxa representa pacientes com isquemia na CPM e níveis de BNP acima de 80 pg/ml. Curva de sobrevida de acordo com os níveis de BNP. A linha azul representa pacientes com níveis de BNP acima de 80 pg/ml e a verde representa pacientes com níveis de BNP abaixo de 80 pg/ml. Curva de sobrevida referente à presença de isquemia (linha verde) ou à ausência de isquemia (linha azul). Discussão

Os últimos 30 anos assistiram a uma busca contínua por novos biomarcadores para diagnóstico, prognóstico, estratificação de risco e tomada de decisão terapêutica em pacientes com dor torácica no setor de emergência. A epidemiologia também é importante na busca por novas técnicas que aceleram o diagnóstico e evitam complicações em pacientes de risco para doenças cardiovasculares, que atualmente apresentam as maiores taxas de morbidade e mortalidade no mundo28-30. Vários biomarcadores foram avaliados no contexto das doenças cardiovasculares, como adrenomedulina, peptídeo natriurético (NT-pro ANP e NT-proBNP), copectina, colina, proteína C-reativa (CRP), o ligante CD40 (CD40L), cistatina C (Cys C), fibrinogênio e, mais recentemente, intermedina30,31. A despeito da existência de vários marcadores, o BNP mostrou-se uma das melhores ferramentas diagnósticas no setor de emergência, não apenas para triagem dos pacientes com queixa de dispneia, mas também para ajudar no diagnóstico e prognóstico daqueles com dor torácica12-14. Dao e cols.32demonstraram que o BNP tem um papel bem estabelecido na avaliação de pacientes com dispneia de etiologia desconhecida no setor de emergência. Naquele estudo, o BNP foi medido em 250 pacientes, cuja queixa principal no setor de emergência era dispneia, tendo os resultados indicado uma significativa discrepância entre os valores de BNP em pacientes com e sem diagnóstico de IC. Vale notar que valores de BNP de 80 pg/ml foram extremamente sensíveis e específicos para o diagnóstico de IC.

O BNP também pode ser usado na avaliação da SCA. Alguns estudos mostraram que após IAM, um alto nível de BNP está associado com infartos mais extensos, maior chance de remodelamento ventricular, menor fração de ejeção e maior risco de IC e morte33-36. Foote e cols.37 sugeriram que a isquemia induzida por exercício e a dosagem dos níveis séricos de NT-pro-BNP e BNP antes e logo após exercício com limitação de sintoma podem distinguir entre pacientes com e sem isquemia, sendo isquemia definida como um defeito reversível na cintilografia com alto grau de acurácia. Uma hipótese é que a isquemia induzida por exercício pode indiretamente causar anormalidades da mobilidade regional da parede, resultando em aumentos nos níveis detectáveis de BNP. Os pacientes com isquemia induzida comparados aos sem isquemia apresentam maiores elevações dos níveis de NT-proBNP e BNP, corroborando aquela hipótese. Assim, um aumento de BNP induzido por exercício pode ser considerado um marcador de isquemia induzida, e esse achado é mais preciso para detectar isquemia do que o infradesnivelamento do segmento ST durante teste de esforço37. Além disso, o valor prognóstico do BNP foi evidenciado em outros estudos. Harrison e cols.38 avaliaram se os níveis de BNP de pacientes chegando ao setor de emergência com dispneia aguda poderiam predizer futuros eventos cardíacos. Tais autores concluíram que naquela população de pacientes com dispneia aguda, os valores de BNP poderiam ser altamente preditivos de eventos cardíacos aos seis meses. Sabatine e cols.16 também demonstraram o valor prognóstico do BNP no contexto de SCA e relataram que um alto nível inicial daquele peptídeo correlaciona-se com risco de morte, IC ou infarto miocárdico aos 30 dias e aos 10 meses. No nosso estudo, um BNP acima de 80 pg/ml foi o mais forte marcador independente para o diagnóstico de isquemia na CPM. Além disso, níveis de BNP acima de 80 pg/ml apresentaram alto poder preditivo para morte, estando associados com um aumento de sete vezes no risco relativo quando comparados a níveis de BNP inferiores àquele valor. Portanto, concordando com dados já publicados, nosso estudo sugere que a implementação da dosagem de BNP possa ser útil na estratificação de risco dos pacientes com dor torácica e com suspeita de SCA sem elevação do segmento ST e troponina negativa39. Um ponto ainda a ser discutido é que, embora nosso estudo tenha demonstrado que níveis altos de BNP correlacionaram-se com pior prognóstico, tais níveis não têm adicional valor preditivo para eventos adversos em pacientes com isquemia. Em recente estudo, Nadir e cols.40 demonstraram que o BNP pode identificar isquemia melhor do que a troponina, mas não relataram os valores preditivos para isquemia miocárdica, o que aumenta ainda mais o valor do nosso estudo.

 Conclusões

O presente estudo demonstrou que pacientes admitidos na emergência com queixa de dor torácica, e que subsequentemente apresentaram isquemia na CPM, tiveram níveis mais elevados de BNP do que aqueles com CPM normal, mostrando a íntima relação do BNP como análise do prognóstico que níveis de BNP acima de 80 pg/ml foram capazes de predizer morte, sendo um marcador útil naquela população.

Fontes de Financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação Acadêmica

Este artigo é parte da dissertação de mestrado de Jader Cunha de Azevedo pelo Programa de Pós-Graduação em Ciências Cardiovasculares - Universidade Federal Fluminense.