Brain natriuretic peptide – a reliable parameter for the effectiveness of cardiac resynchronization therapy after coronary artery bypass gra
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《血管的通路杂志》
Clinic of Cardiothoracic Surgery, Klinikum Augsburg, Stenglinstr. 2, 86156 Augsburg, Germany
Presented at the 54th International Congress of the European Society for Cardiovascular Surgery, Athens, Greece, May 19–22, 2005.
Abstract
Objectives: Brain natriuretic peptide (BNP) is a valuable marker in heart failure and its therapy, for example cardiac resynchronization therapy (CRT). So far, one finding which is indicative for CRT is dyssynchronity of ventricular contraction obtained by echocardiography. The aim of this study was to show that BNP is also a helpful marker to help decide whether CRT is useful for patients after CABG. Methods: Forty-two patients with a poor ejection fraction (<35%) underwent elective CABG. Twenty-eight of them received permanent biventricular stimulation for seven days after surgery. Before and on the first, third, seventh and tenth day after surgical treatment, the following parameters were established: left ventricular function obtained by transthoracic echocardiography, myocardium-specific enzymes (such as CK and CKMB), ECG and BNP. Results: There was a very good correlation between the preoperative ejection fraction and BNP (r2=0.98, P<0.005). Patients who had received CRT after CABG had BNP levels similar to preoperative data on postoperative day 7. This decrease of the BNP values in the CRT-group is in accord with an increased left ventricular function as obtained by echocardiography. The control group, which had not received CRT, showed significantly higher BNP levels. Conclusions: Therefore, we conclude that BNP is a good marker to evaluate CRT in patients undergoing CABG. An extraordinary rise of the BNP level should lead to early therapeutic consequences like CRT. The significantly lower BNP level of the patients with heart failure who received CRT indicates a better prognosis.
Key Words: Cardiac resynchronization therapy (CRT); Heart failure; Brain natriuretic peptide (BNP); Coronary artery bypass grafting (CABG)
1. Introduction
During the last decade there is a growing number of patients, who are borderline cases in cardiac surgery due to their co-morbidity. Especially, heart failure increases mortality and morbidity in surgical procedures. Therefore, these patients need special risk stratification and perioperative management.
To estimate perioperative mortality certain score systems have been developed. In Europe the EuroSCORE [1] is commonly used. The risk factor for heart failure is reflected in left ventricular function. However, the score system gives no hint at the prognosis of the heart failure itself.
The family of natriuretic peptides are good humoral factors to estimate heart failure. Despite the firstly detected atrial natriuretic peptide (ANP) [2], the most important one is BNP (B-type natriuretic peptide or brain natriuretic peptide) which was discovered seven years later [3]. Studies have shown that BNP is superior to ANP in the diagnosis of heart failure [4]. Additionally, Tsutamoto and coworkers [5] have shown that BNP was the best marker to assess the prognosis of patients suffering from chronic heart failure independent from hemodynamic parameters such as LVEF or pulmonary capillary wedge pressure. Therefore, we suggest that BNP should be an additional factor for risk stratification of patients with poor LVEF before cardiac surgery.
As mentioned before, these patients with heart failure need additional perioperative management to keep the perioperative mortality low. One therapeutic option in chronic heart failure is cardiac resynchronization therapy (CRT). The principle of this treatment is the resynchronization of the asynchronous contraction of the left and the right ventricle [6,7]. In comparison to the placing of the left ventricular wire during a catheter intervention, the placing of the wire epicardially throughout a cardiac procedure, e.g. coronary artery bypass grafting, can be performed rather easily.
So far a left bundle branch block has been an indispensable requirement. But recently, Auricchio and Yu [8] have suggested that the main requirement for the effectiveness of CRT is the dyssynchronity between the left and right ventricle. They mention that systolic dyssynchronity exists in many patients with heart failure irrespective of QRS duration. Therefore, the main device to assess the usefulness of CRT is echocardiography.
Our aim was, therefore, to prove the usefulness of the measurement of BNP plasma levels to assess the benefit of CRT in patients after CABG [9]. To measure the benefit for these patients, we use echocardiographic parameters and the measurement of BNP plasma levels. These two independent tests are used to test the reliability of measurement of BNP levels.
While echocardiography is investigator dependent, the measurement of BNP plasma levels is independent from the investigator. The other advantage of BNP measurement in contrast to echocardiography is its easy assessment.
2. Materials and methods
2.1. Study group
The study was performed in a prospectively randomized way. All patients provided written consent. The protocol was approved by Ethik Kommission Freiburg. Three groups of consecutive patients were formed (Table 1). The patients were allocated to V- or 0-groups according to their EF. Patients who had a normal or only slightly reduced ejection fraction (EF>35%) were allocated to the 0-group. If their EF was below 35%, they were allocated to the V-groups and randomized as to whether they received CRT (V1-group) or not (V2-group).
The criteria for inclusion in and exclusion from the study are shown in Table 2. We strongly hold that a bundle branch block was an exclusion criterion. So far, a bundle branch block with QRS duration longer than 120 to 150 ms (130 ms) [10] has been necessary for the implantation of a CRT device. The patients included in this study were between 18 and 75 years of age. They provided written informed consent. Left ventricular function was assessed with the help of transthoracic echocardiography. A good renal function and no need for blood transfusion prior to CABG were important to obtain valid BNP-levels.
Before (day 0) and after surgical procedure (days 1, 3, 7 and 10) among others BNP-level and left ventricular function obtained with transthoracic echocardiography were measured. The measurement of BNP-levels was done by test kit of Biosite Diagnostics Inc. (Triage BNP-Test, Biosite Diagnostics Inc., San Diego, CA, USA). The protocol is shown in Table 3.
2.2. Implantation and pacing protocol
All patients received on-pump coronary artery bypass grafting. With revascularization performed, the implantation of epicardial temporal leads (Osypca Medical GmbH, Berlin, Germany) was done during the reperfusion of the myocardium. The leads were placed in the lateral wall of the right atrium and the anterior wall of the right ventricle (V2-group), and additionally, in the lateral wall of the left ventricle (V1-group, 0-group). We took care not to place the leads into an infarcted area. Afterwards the leads were connected to an external pacing device (Osypka PACE 203H, Osypka Medical GmbH, Berlin, Germany).
The pacing of the heart was done in different ways according to the various groups: In the V1- and the 0-group we stimulated the heart with 90 bpm AV sequentially. No interventricular delay was possible due to only one-ventricular connection of the Osypka PACE 203H. Up to day 1, we performed an atrially triggered VAT-stimulation with AV duration of 130 ms. There should be a heart rate of at least 60 bpm. We chose this short AV duration to guarantee biventricular stimulation. Stimulation was done up to day 7 and the epicardial leads were removed afterwards.
In group 0, we performed demand stimulation with a heart rate of 90 bpm on day 0 and at least 60 bpm up to day 7. On this day also the leads were removed.
2.3. Data analysis
Statistical analysis was performed by use of commercial software (SigmaStat 2.03, SPSS Inc.). Comparison of data was done with Student's t-test (EF by echocardiography), Mann–Whitney Rank Sum test, where normality-test failed, or 2-test. Unless otherwise noted, all data are reported as mean±standard deviation.
3. Results
So far 42 patients have been included in the study (16 in V1, 14 in V2, 12 in 0). One person of the 0-group died due to a fatal myocardial infarction of the anterior wall. A post mortem analysis showed an early closure of the mammary artery bypass to the left anterior descendent artery. This adverse event was, therefore, classified non-CRT related.
The 0-group was closed after the inclusion of 12 patients. A mid-term analysis showed a worsening of left ventricular function during biventricular stimulation. So we stopped biventricular stimulation in this group. Echocardiographic analysis showed that these patients had no dyssynchronity of left ventricular movement without stimulation, meaning that cardiac resynchronization therapy cannot improve normal left ventricular contraction. It can even worsen the left ventricular function. So in this group CRT is not recommended.
3.1. Improvement of left ventricular function
In contrast to no benefit in left ventricular function due to CRT in the 0-Group, there is a real benefit in left ventricular function in the V1-group. Fig. 1 shows the development of LVEF for 10 days. The LVEF is measured by transthoracic echocardiography. Curves for each group are depicted.
As mentioned above, the EF of the 0-group decreased from 62.5±8.0 to 50.7±12.6 on the first postoperative day and 48.9±11.6 on the third postoperative day during biventricular simulation. There was a slight recovery, although not a significant one, after the end of stimulation. On discharge from the hospital the EF was 53.5±8.1.
The more interesting groups herein are the V-groups. Before surgery there was no difference in EF between the V1 and V2 groups (28.3±6.5 for V1 and 29.3±4.5 for V2). But there was better EF in the V1 group during biventricular stimulation. This increase was statistically significant on postoperative days 1 and 3 (day 1: 35.8±4.7 V1-group vs. 25.7±3.5 V2-group, P=0.002 and day 3: 35.7±3.3 V1-group vs. 25.9±1.9 V2-group, P<0.001). After the omission of the stimulation the EF of both groups were at least close (day 7: 29.6±5.8 V1-group vs. 25.0±2.9 V2-group and day 10: 27.3±6.1 V1-group vs. 28.6±6.3 V2-group). There was a slightly better EF within the V1-group on day 7 immediately after the end of CRT, although no statistical significance could be established.
To complete this description of the EF in the V1-group, it also has to be mentioned that one patient did not benefit from CRT. There was a decrease in cardiac output and lower EF during biventricular stimulation. This patient did not show the signs of septal deviation in echocardiography. In this patient, we stopped biventricular stimulation immediately after surgery.
According to the exclusion criteria for this study none of the patients had a left bundle branch block preoperatively. Likewise, none of the patients in each group developed a bundle branch block postoperatively. We also investigated whether a continuous atrially triggered stimulation of the left and right ventricle causes less atrial fibrillation postoperatively. However, there was no difference between groups V1 and V2. So CRT is not protective against atrial fibrillation. On the other hand, CRT is not responsible for a higher rate of postoperative atrial fibrillation.
Due to the better EF in the V1-group the stay in ICU was shorter in this group than in the V2-group. There was no difference in the postoperative stay in hospital overall because according to the protocol the patients stayed in hospital at least until day 10, which almost corresponds to the normal time of discharge.
3.2. BNP plasma levels
The first task in this study was to evaluate whether BNP-levels are reliable markers after coronary artery bypass grafting. The problem is that after surgery there are many factors influencing BNP plasma levels. There is an altered renal function causing volume overload and higher preload. This leads to an increased stress on the ventricular wall corresponding with higher BNP plasma levels. The impaired renal function also influences the metabolism of the peptide hormone BNP itself leading to increased levels. In the same way a shift in volume takes place, due to diuretics or volume substitution, immediately prior to BNP measurement influence on its plasma levels. Therefore, our first aim was to prove whether the measured values are reliable and reflect ventricular function.
As mentioned before, earlier findings indicated a good correlation between EF and BNP plasma levels. So, we correlated BNP and EF. The result is summarized in Fig. 2. Before surgery there was a very good correlation between EF and BNP (r2=0.98, P<0.005), but after surgery, especially on days 1 and 3, there was almost no correlation between these two parameters. Up to day 7 there again was a good correlation between the two parameters. However, only on day 10 was the slope almost equal to day 0. Therefore, we conclude that BNP values before surgery and up to day 7 are reliable.
Mean and standard deviations of the various BNP plasma level values for each of the three groups during the different days are depicted in Fig. 3. All the groups showed a significant increase within their group on the first postoperative day. But only the biventricular-paced groups (0-group and V1-group) show the same BNP values on postoperative day 10 as before surgery. In the V2-group, there is a statistical difference (P=0.038) between day 0 (presurgery, 434±149 pg/ml) and postoperative day 10 (944±365 pg/ml). There is also a statistically significant difference between the V1-group and the V2-group on postoperative day 10 (P=0.034, Mann–Whitney Rank Sum test).
There was no correlation between myocardium specific enzymes as creatininkinase (CK or CK (MB)) and troponine. Only a severe myocardial infarction leads to an enormous increase of these enzymes and BNP as well.
4. Discussion
The number of patients suffering from heart failure still increases. Despite a very useful but limited medical therapy, heart transplantation or the implantation of a ventricular assist device are the more invasive (and expensive) alternatives. Approximately 10 years ago cardiac resynchronization therapy (CRT) became an interesting and less invasive additive therapeutic option. But, so far one condition sine qua non for CRT has been a left bundle branch block.
4.1. Is CRT useful after CABG
In our group of patients, which had poor LVEF before CABG, none had a bundle branch block before or after surgery. But all these patients except one benefited from CRT. So in our opinion CRT is a good therapeutic option. The question is therefore, what the underlying mechanism of this therapy in our patients is. So far, all the patients with a left bundle branch block have profited from CRT due to their conduction delay in the left bundle branch. This results in an asynchronous contraction of the left and right ventricle. CRT forces the contraction of both ventricles into simultaneity by overdriving the left bundle branch.
In most of the patients of the V1- and V2-groups, we saw two echocardiographic findings in common: dyskinetic septal movement and left ventricular dilation. Our explanation of the benefit in the V1-group patients is an existing conduction delay, too. However, this delay is not related in the bundle branch but further downstream. We think that the delay is in the dilated myocardium resulting in a time shift of left- and right-ventricular contraction. So there is an interventricular delay of the contraction.
A second reason is to be found in the abnormal septal movement. This dyssynchronity in intraventricular contraction could be easily detected in transthoracic echocardiography. This phenomenon is commonly known, but its reasons are not completely understood. Cardioplegic solutions and a poor vascularization of the septum are often held responsible for this mechanism. It is very impressive to detect the reversibility of this abnormal movement during CRT. A sketch of this change in ventricular contraction is shown in Fig. 4.
4.2. Is the measurement of BNP plasma levels a reliable test
The peptide hormone BNP is a commonly used parameter to estimate the severity of heart failure and its prognosis. But its usefulness in cardiac surgery is yet unknown. As mentioned before, there are many factors influencing the amount of BNP in plasma. Shift of intravascular volume, use of diuretics, catecholamine administration and edematous myocardium after surgery are some of them. Therefore, we first investigated its reliability in cardiac surgery.
The analysis of the correlation BNP versus EF showed almost no correlation on days one and three. Therefore, we conclude that BNP does not depict the ventricular function in these early postoperative days. Then it is influenced by too many factors. But, on the other hand, reflecting the course of the BNP values during the postoperative period (Fig. 3), its shape is almost the same in all groups (and each patient). An extraordinary rise of BNP values should lead consecutively to therapeutic consequences such as positive inotropic medication or CRT. The limit of the relative rise of the BNP values cannot be derived from this small amount of patients. However, we estimate a rise of about three times the preoperative value should be up to day seven there is as good a correlation between EF and BNP as preoperatively. But only on day 10 are the slopes of these correlations mentioned equal as abnormal.
4.3. Which information do we get from the BNP plasma level
In accordance to these findings we conclude that up to day 10 – with concession day 7 – the BNP levels depict the EF of the patients. Then BNP again is as good a predictive value of heart failure as preoperatively. And this is the main purpose of BNP to predict the prognosis of heart failure. It is shown in many studies, that there is a certain limit for BNP plasma values to distinguish the groups of patients with good or poor prognosis [5]. And it has also been shown, that patients can change these groups of prediction by enhancing or worsening their heart failure. The ranking into these groups is done by measuring BNP.
In our study patients who received CRT had a significantly lower level of BNP than patients who did not receive CRT. Consecutively the prognosis of these patients who underwent CRT should be better.
Reflecting these findings, a positive effect of CRT can be seen in this study. Of the groups with a poor EF only the one which received CRT reached BNP levels like the preoperative ones. There was also a higher BNP level in the patients who did not receive CRT on day 10. This indicates that the prognosis in the patients with CRT is better.
According to all the guidelines of the different societies of cardiology for administration of CRT a left bundle branch block must be prevalent. The underlying mechanisms are understood and there is good evidence [11]. But in this special group of patients (V1) who underwent coronary artery bypass grafting, CRT is also useful according to our study. This is shown in our study with the help of measuring BNP plasma levels.
Acknowledgements
This study was kindly supported by St. Jude Medical.
References
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Presented at the 54th International Congress of the European Society for Cardiovascular Surgery, Athens, Greece, May 19–22, 2005.
Abstract
Objectives: Brain natriuretic peptide (BNP) is a valuable marker in heart failure and its therapy, for example cardiac resynchronization therapy (CRT). So far, one finding which is indicative for CRT is dyssynchronity of ventricular contraction obtained by echocardiography. The aim of this study was to show that BNP is also a helpful marker to help decide whether CRT is useful for patients after CABG. Methods: Forty-two patients with a poor ejection fraction (<35%) underwent elective CABG. Twenty-eight of them received permanent biventricular stimulation for seven days after surgery. Before and on the first, third, seventh and tenth day after surgical treatment, the following parameters were established: left ventricular function obtained by transthoracic echocardiography, myocardium-specific enzymes (such as CK and CKMB), ECG and BNP. Results: There was a very good correlation between the preoperative ejection fraction and BNP (r2=0.98, P<0.005). Patients who had received CRT after CABG had BNP levels similar to preoperative data on postoperative day 7. This decrease of the BNP values in the CRT-group is in accord with an increased left ventricular function as obtained by echocardiography. The control group, which had not received CRT, showed significantly higher BNP levels. Conclusions: Therefore, we conclude that BNP is a good marker to evaluate CRT in patients undergoing CABG. An extraordinary rise of the BNP level should lead to early therapeutic consequences like CRT. The significantly lower BNP level of the patients with heart failure who received CRT indicates a better prognosis.
Key Words: Cardiac resynchronization therapy (CRT); Heart failure; Brain natriuretic peptide (BNP); Coronary artery bypass grafting (CABG)
1. Introduction
During the last decade there is a growing number of patients, who are borderline cases in cardiac surgery due to their co-morbidity. Especially, heart failure increases mortality and morbidity in surgical procedures. Therefore, these patients need special risk stratification and perioperative management.
To estimate perioperative mortality certain score systems have been developed. In Europe the EuroSCORE [1] is commonly used. The risk factor for heart failure is reflected in left ventricular function. However, the score system gives no hint at the prognosis of the heart failure itself.
The family of natriuretic peptides are good humoral factors to estimate heart failure. Despite the firstly detected atrial natriuretic peptide (ANP) [2], the most important one is BNP (B-type natriuretic peptide or brain natriuretic peptide) which was discovered seven years later [3]. Studies have shown that BNP is superior to ANP in the diagnosis of heart failure [4]. Additionally, Tsutamoto and coworkers [5] have shown that BNP was the best marker to assess the prognosis of patients suffering from chronic heart failure independent from hemodynamic parameters such as LVEF or pulmonary capillary wedge pressure. Therefore, we suggest that BNP should be an additional factor for risk stratification of patients with poor LVEF before cardiac surgery.
As mentioned before, these patients with heart failure need additional perioperative management to keep the perioperative mortality low. One therapeutic option in chronic heart failure is cardiac resynchronization therapy (CRT). The principle of this treatment is the resynchronization of the asynchronous contraction of the left and the right ventricle [6,7]. In comparison to the placing of the left ventricular wire during a catheter intervention, the placing of the wire epicardially throughout a cardiac procedure, e.g. coronary artery bypass grafting, can be performed rather easily.
So far a left bundle branch block has been an indispensable requirement. But recently, Auricchio and Yu [8] have suggested that the main requirement for the effectiveness of CRT is the dyssynchronity between the left and right ventricle. They mention that systolic dyssynchronity exists in many patients with heart failure irrespective of QRS duration. Therefore, the main device to assess the usefulness of CRT is echocardiography.
Our aim was, therefore, to prove the usefulness of the measurement of BNP plasma levels to assess the benefit of CRT in patients after CABG [9]. To measure the benefit for these patients, we use echocardiographic parameters and the measurement of BNP plasma levels. These two independent tests are used to test the reliability of measurement of BNP levels.
While echocardiography is investigator dependent, the measurement of BNP plasma levels is independent from the investigator. The other advantage of BNP measurement in contrast to echocardiography is its easy assessment.
2. Materials and methods
2.1. Study group
The study was performed in a prospectively randomized way. All patients provided written consent. The protocol was approved by Ethik Kommission Freiburg. Three groups of consecutive patients were formed (Table 1). The patients were allocated to V- or 0-groups according to their EF. Patients who had a normal or only slightly reduced ejection fraction (EF>35%) were allocated to the 0-group. If their EF was below 35%, they were allocated to the V-groups and randomized as to whether they received CRT (V1-group) or not (V2-group).
The criteria for inclusion in and exclusion from the study are shown in Table 2. We strongly hold that a bundle branch block was an exclusion criterion. So far, a bundle branch block with QRS duration longer than 120 to 150 ms (130 ms) [10] has been necessary for the implantation of a CRT device. The patients included in this study were between 18 and 75 years of age. They provided written informed consent. Left ventricular function was assessed with the help of transthoracic echocardiography. A good renal function and no need for blood transfusion prior to CABG were important to obtain valid BNP-levels.
Before (day 0) and after surgical procedure (days 1, 3, 7 and 10) among others BNP-level and left ventricular function obtained with transthoracic echocardiography were measured. The measurement of BNP-levels was done by test kit of Biosite Diagnostics Inc. (Triage BNP-Test, Biosite Diagnostics Inc., San Diego, CA, USA). The protocol is shown in Table 3.
2.2. Implantation and pacing protocol
All patients received on-pump coronary artery bypass grafting. With revascularization performed, the implantation of epicardial temporal leads (Osypca Medical GmbH, Berlin, Germany) was done during the reperfusion of the myocardium. The leads were placed in the lateral wall of the right atrium and the anterior wall of the right ventricle (V2-group), and additionally, in the lateral wall of the left ventricle (V1-group, 0-group). We took care not to place the leads into an infarcted area. Afterwards the leads were connected to an external pacing device (Osypka PACE 203H, Osypka Medical GmbH, Berlin, Germany).
The pacing of the heart was done in different ways according to the various groups: In the V1- and the 0-group we stimulated the heart with 90 bpm AV sequentially. No interventricular delay was possible due to only one-ventricular connection of the Osypka PACE 203H. Up to day 1, we performed an atrially triggered VAT-stimulation with AV duration of 130 ms. There should be a heart rate of at least 60 bpm. We chose this short AV duration to guarantee biventricular stimulation. Stimulation was done up to day 7 and the epicardial leads were removed afterwards.
In group 0, we performed demand stimulation with a heart rate of 90 bpm on day 0 and at least 60 bpm up to day 7. On this day also the leads were removed.
2.3. Data analysis
Statistical analysis was performed by use of commercial software (SigmaStat 2.03, SPSS Inc.). Comparison of data was done with Student's t-test (EF by echocardiography), Mann–Whitney Rank Sum test, where normality-test failed, or 2-test. Unless otherwise noted, all data are reported as mean±standard deviation.
3. Results
So far 42 patients have been included in the study (16 in V1, 14 in V2, 12 in 0). One person of the 0-group died due to a fatal myocardial infarction of the anterior wall. A post mortem analysis showed an early closure of the mammary artery bypass to the left anterior descendent artery. This adverse event was, therefore, classified non-CRT related.
The 0-group was closed after the inclusion of 12 patients. A mid-term analysis showed a worsening of left ventricular function during biventricular stimulation. So we stopped biventricular stimulation in this group. Echocardiographic analysis showed that these patients had no dyssynchronity of left ventricular movement without stimulation, meaning that cardiac resynchronization therapy cannot improve normal left ventricular contraction. It can even worsen the left ventricular function. So in this group CRT is not recommended.
3.1. Improvement of left ventricular function
In contrast to no benefit in left ventricular function due to CRT in the 0-Group, there is a real benefit in left ventricular function in the V1-group. Fig. 1 shows the development of LVEF for 10 days. The LVEF is measured by transthoracic echocardiography. Curves for each group are depicted.
As mentioned above, the EF of the 0-group decreased from 62.5±8.0 to 50.7±12.6 on the first postoperative day and 48.9±11.6 on the third postoperative day during biventricular simulation. There was a slight recovery, although not a significant one, after the end of stimulation. On discharge from the hospital the EF was 53.5±8.1.
The more interesting groups herein are the V-groups. Before surgery there was no difference in EF between the V1 and V2 groups (28.3±6.5 for V1 and 29.3±4.5 for V2). But there was better EF in the V1 group during biventricular stimulation. This increase was statistically significant on postoperative days 1 and 3 (day 1: 35.8±4.7 V1-group vs. 25.7±3.5 V2-group, P=0.002 and day 3: 35.7±3.3 V1-group vs. 25.9±1.9 V2-group, P<0.001). After the omission of the stimulation the EF of both groups were at least close (day 7: 29.6±5.8 V1-group vs. 25.0±2.9 V2-group and day 10: 27.3±6.1 V1-group vs. 28.6±6.3 V2-group). There was a slightly better EF within the V1-group on day 7 immediately after the end of CRT, although no statistical significance could be established.
To complete this description of the EF in the V1-group, it also has to be mentioned that one patient did not benefit from CRT. There was a decrease in cardiac output and lower EF during biventricular stimulation. This patient did not show the signs of septal deviation in echocardiography. In this patient, we stopped biventricular stimulation immediately after surgery.
According to the exclusion criteria for this study none of the patients had a left bundle branch block preoperatively. Likewise, none of the patients in each group developed a bundle branch block postoperatively. We also investigated whether a continuous atrially triggered stimulation of the left and right ventricle causes less atrial fibrillation postoperatively. However, there was no difference between groups V1 and V2. So CRT is not protective against atrial fibrillation. On the other hand, CRT is not responsible for a higher rate of postoperative atrial fibrillation.
Due to the better EF in the V1-group the stay in ICU was shorter in this group than in the V2-group. There was no difference in the postoperative stay in hospital overall because according to the protocol the patients stayed in hospital at least until day 10, which almost corresponds to the normal time of discharge.
3.2. BNP plasma levels
The first task in this study was to evaluate whether BNP-levels are reliable markers after coronary artery bypass grafting. The problem is that after surgery there are many factors influencing BNP plasma levels. There is an altered renal function causing volume overload and higher preload. This leads to an increased stress on the ventricular wall corresponding with higher BNP plasma levels. The impaired renal function also influences the metabolism of the peptide hormone BNP itself leading to increased levels. In the same way a shift in volume takes place, due to diuretics or volume substitution, immediately prior to BNP measurement influence on its plasma levels. Therefore, our first aim was to prove whether the measured values are reliable and reflect ventricular function.
As mentioned before, earlier findings indicated a good correlation between EF and BNP plasma levels. So, we correlated BNP and EF. The result is summarized in Fig. 2. Before surgery there was a very good correlation between EF and BNP (r2=0.98, P<0.005), but after surgery, especially on days 1 and 3, there was almost no correlation between these two parameters. Up to day 7 there again was a good correlation between the two parameters. However, only on day 10 was the slope almost equal to day 0. Therefore, we conclude that BNP values before surgery and up to day 7 are reliable.
Mean and standard deviations of the various BNP plasma level values for each of the three groups during the different days are depicted in Fig. 3. All the groups showed a significant increase within their group on the first postoperative day. But only the biventricular-paced groups (0-group and V1-group) show the same BNP values on postoperative day 10 as before surgery. In the V2-group, there is a statistical difference (P=0.038) between day 0 (presurgery, 434±149 pg/ml) and postoperative day 10 (944±365 pg/ml). There is also a statistically significant difference between the V1-group and the V2-group on postoperative day 10 (P=0.034, Mann–Whitney Rank Sum test).
There was no correlation between myocardium specific enzymes as creatininkinase (CK or CK (MB)) and troponine. Only a severe myocardial infarction leads to an enormous increase of these enzymes and BNP as well.
4. Discussion
The number of patients suffering from heart failure still increases. Despite a very useful but limited medical therapy, heart transplantation or the implantation of a ventricular assist device are the more invasive (and expensive) alternatives. Approximately 10 years ago cardiac resynchronization therapy (CRT) became an interesting and less invasive additive therapeutic option. But, so far one condition sine qua non for CRT has been a left bundle branch block.
4.1. Is CRT useful after CABG
In our group of patients, which had poor LVEF before CABG, none had a bundle branch block before or after surgery. But all these patients except one benefited from CRT. So in our opinion CRT is a good therapeutic option. The question is therefore, what the underlying mechanism of this therapy in our patients is. So far, all the patients with a left bundle branch block have profited from CRT due to their conduction delay in the left bundle branch. This results in an asynchronous contraction of the left and right ventricle. CRT forces the contraction of both ventricles into simultaneity by overdriving the left bundle branch.
In most of the patients of the V1- and V2-groups, we saw two echocardiographic findings in common: dyskinetic septal movement and left ventricular dilation. Our explanation of the benefit in the V1-group patients is an existing conduction delay, too. However, this delay is not related in the bundle branch but further downstream. We think that the delay is in the dilated myocardium resulting in a time shift of left- and right-ventricular contraction. So there is an interventricular delay of the contraction.
A second reason is to be found in the abnormal septal movement. This dyssynchronity in intraventricular contraction could be easily detected in transthoracic echocardiography. This phenomenon is commonly known, but its reasons are not completely understood. Cardioplegic solutions and a poor vascularization of the septum are often held responsible for this mechanism. It is very impressive to detect the reversibility of this abnormal movement during CRT. A sketch of this change in ventricular contraction is shown in Fig. 4.
4.2. Is the measurement of BNP plasma levels a reliable test
The peptide hormone BNP is a commonly used parameter to estimate the severity of heart failure and its prognosis. But its usefulness in cardiac surgery is yet unknown. As mentioned before, there are many factors influencing the amount of BNP in plasma. Shift of intravascular volume, use of diuretics, catecholamine administration and edematous myocardium after surgery are some of them. Therefore, we first investigated its reliability in cardiac surgery.
The analysis of the correlation BNP versus EF showed almost no correlation on days one and three. Therefore, we conclude that BNP does not depict the ventricular function in these early postoperative days. Then it is influenced by too many factors. But, on the other hand, reflecting the course of the BNP values during the postoperative period (Fig. 3), its shape is almost the same in all groups (and each patient). An extraordinary rise of BNP values should lead consecutively to therapeutic consequences such as positive inotropic medication or CRT. The limit of the relative rise of the BNP values cannot be derived from this small amount of patients. However, we estimate a rise of about three times the preoperative value should be up to day seven there is as good a correlation between EF and BNP as preoperatively. But only on day 10 are the slopes of these correlations mentioned equal as abnormal.
4.3. Which information do we get from the BNP plasma level
In accordance to these findings we conclude that up to day 10 – with concession day 7 – the BNP levels depict the EF of the patients. Then BNP again is as good a predictive value of heart failure as preoperatively. And this is the main purpose of BNP to predict the prognosis of heart failure. It is shown in many studies, that there is a certain limit for BNP plasma values to distinguish the groups of patients with good or poor prognosis [5]. And it has also been shown, that patients can change these groups of prediction by enhancing or worsening their heart failure. The ranking into these groups is done by measuring BNP.
In our study patients who received CRT had a significantly lower level of BNP than patients who did not receive CRT. Consecutively the prognosis of these patients who underwent CRT should be better.
Reflecting these findings, a positive effect of CRT can be seen in this study. Of the groups with a poor EF only the one which received CRT reached BNP levels like the preoperative ones. There was also a higher BNP level in the patients who did not receive CRT on day 10. This indicates that the prognosis in the patients with CRT is better.
According to all the guidelines of the different societies of cardiology for administration of CRT a left bundle branch block must be prevalent. The underlying mechanisms are understood and there is good evidence [11]. But in this special group of patients (V1) who underwent coronary artery bypass grafting, CRT is also useful according to our study. This is shown in our study with the help of measuring BNP plasma levels.
Acknowledgements
This study was kindly supported by St. Jude Medical.
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