|Year : 2020 | Volume
| Issue : 3 | Page : 121-127
Evaluation of N-terminal pro B-type natriuretic peptide and echocardiographic parameters in congestive heart failure patients with pre- and post-cardiac resynchronization therapy
Amrendra Pandey1, Praveen Singh2, Vrishank Bajaj2, Smita Gulati3, Michelle Siew4
1 Department of Cardiac Services, Dharamshila Narayan Hridayala Hospital, Delhi, India
2 Department of Cardiology, Rajiv Gandhi Super Specialty Hospital, Delhi, India
3 Department of Anesthesiology, Rajiv Gandhi Super Specialty Hospital, Delhi, India
4 Department of Critical Care, Rajiv Gandhi Super Specialty Hospital, Delhi, India
|Date of Submission||04-Jul-2020|
|Date of Decision||12-Aug-2020|
|Date of Acceptance||09-Sep-2020|
|Date of Web Publication||23-Dec-2020|
Dr. Praveen Singh
Rajiv Gandhi Super Specialty Hospital, Delhi
Source of Support: None, Conflict of Interest: None
Introduction: Cardiac resynchronization therapy (CRT) has rapidly evolved as a standard therapy for heart failure (HF) patients. Higher levels of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are typically used in the diagnosis of HF. Materials and Methods: A prospective, observational study of 60 patients with CRT was evaluated with clinical, laboratory and echocardiographic parameters. All patients underwent clinical examination, 6-min walk test, 12-lead electrocardiogram, two-dimensional echocardiographic with Doppler evaluations and NT-proBNP determination. Results: After effective CRT in patients, there was significant improvements in New York Heart Association functional class and 6-min walked distance along with significant decrease in mean QRS width and NT-proBNP plasma levels at 3 and 6 months' follow-up (P < 0.05). The repeat echocardiogram at 3 and 6 months' follow-up showed a significant reduction in the left ventricular end-systolic volume, left ventricular end diastolic volume, and significant left ventricular ejection fraction (LVEF) improvement (P < 0.05). No significant reduction in left ventricle (LV) diameters over 3 and 6 months' follow-up with a significant reduction in the MR severity after 6 months were observed (P < 0.05). At 6 months' follow-up, 75% patients (n = 45) were responders showing concordance between clinical, echocardiographic and NT-proBNP definitions of CRT response while 25% patients (n = 15) were nonresponders. The change in NT-proBNP levels between pre-CRT and 6 months' post CRT was significantly more important in responders than in nonresponders (P < 0.001). Conclusion: The present study shows the clinical benefit of treating patients with CRT and points to the reverse ventricular remodeling, with sustained decrease in LV volumes, plasma NT-proBNP, increase in LVEF, and decrease of the severity of mitral valve regurgitation.
Keywords: Cardiac resynchronization therapy, left ventricular ejection fraction, N-terminal pro B-type natriuretic peptide, QRS
|How to cite this article:|
Pandey A, Singh P, Bajaj V, Gulati S, Siew M. Evaluation of N-terminal pro B-type natriuretic peptide and echocardiographic parameters in congestive heart failure patients with pre- and post-cardiac resynchronization therapy. J Indian coll cardiol 2020;10:121-7
|How to cite this URL:|
Pandey A, Singh P, Bajaj V, Gulati S, Siew M. Evaluation of N-terminal pro B-type natriuretic peptide and echocardiographic parameters in congestive heart failure patients with pre- and post-cardiac resynchronization therapy. J Indian coll cardiol [serial online] 2020 [cited 2021 Jan 18];10:121-7. Available from: https://www.joicc.org/text.asp?2020/10/3/121/304377
| Introduction|| |
Heart failure (HF) is a complex syndrome of heart; caused not only by contractile force reduction, but also by neurohormonal changes affecting sympathetic and parasympathetic tone and the renin-angiotensin-aldosterone system., HF, a global epidemic, affecting 23 million people worldwide is characterized by cardiac remodeling, i.e., gradual dilation of the left ventricle (LV) and consequent loss of contractile function.
There have been many advances in the pharmacological and non-pharmacological management of HF over the years, yet the prognosis of severe HF remains poor.,, In response to this unmet need, recent years have seen dramatic improvements in device-based therapy targeting one cause of systolic dysfunction-dyssynchronous ventricular contraction.
Cardiac resynchronization therapy (CRT) is an effective non-pharmacological treatment for patients with advanced drug refractory HF and electromechanical asynchrony. Large multicenter clinical trials such as the cardiac resynchronization in HF (CARE-HF) study and the Comparison of Medical Therapy, Pacing, and Defibrillation in HF (COMPANION) trial demonstrated that CRT could improve the LV function electrically and mechanically.,, CRT restores mechanical synchrony by electrically activating the heart and makes the left and right ventricle to contract simultaneously using cardiac pacing in asynchronous hearts.
CRT also improves HF symptoms and exercise capacity in appropriately selected patients and also reduces mortality, morbidity, and hospitalization due to decompensated HF.,,, Nevertheless, despite appropriate case selection, approximately 20%–30% of patients do not respond to CRT.,
B-type natriuretic peptide (BNP) and the inactive amino terminal fragment, N-terminal proBNP (NT-proBNP), are synthesized in the ventricular myocardium and released in response to volume expansion or pressure overload., The severity of HF is characterized by the higher levels of BNP and NT-proBNP. These markers are also valuable for the monitoring of the response to treatment.,, Consequently, the plasma level can theoretically change rapidly in response to hemodynamic changes.
In reverse remodeling process, neurohumoral activity is reduced and the decrease in plasma BNP after initiation of CRT may predict clinical improvement during the follow-up. The present study was therefore conducted to evaluate the effect of CRT implantation on level of NT-proBNP and to correlate clinical and echocardiographic efficacy of CRT with change in NT-proBNP level.
| Materials and Methods|| |
This was a prospective, observational study conducted from June 2015 to November 2016 for a total duration of 18 months, with follow-up at 3 and 6 months among CRT patients admitted in Max Super Specialty Hospital, Saket and Patparganj, New Delhi.
The study was conducted in accordance with the approval from Institutional Ethical Committee of Max Super Specialty Hospital. Informed written consent was obtained from patients preserving confidentiality about the subjects of the study. All the patients during the study received utmost care.
The criteria of inclusion consists of HF patients undergoing CRT as per the standard criteria, i.e., patient in New York Heart Association (NYHA) functional class III and ambulatory class IV who remained symptomatic despite optimal pharmacological treatment along with left ventricular ejection fraction (LVEF) ≤35% and wide QRS ≥120 ms with a left bundle branch block (LBBB) pattern in sinus rhythm or QRS ≥150 ms with or without LBBB pattern. Patients with comorbidities and/or frailty limit survival with good functional capacity to <1 year, chronic atrial fibrillation, acute coronary syndrome (within 1 month), and right bundle branch block are excluded from the study.
The present study was a prospective, observational study where all patients with CRT were evaluated with clinical, laboratory, and echocardiographic parameters. Between 10 and 1 day before CRT implantation, all patients underwent clinical examination; 6 min walk test, 12-lead electrocardiogram (ECG) (to assess QRS interval), two-dimensional echocardiographic, Doppler evaluations (to assess the LVEF, the internal diastolic dimensions, and the degree of mitral regurgitation), and NT-proBNP determination. Three monthly follow-up for a total duration of 6 months was done with all the laboratory investigations and echocardiography as framed in the protocol.
Primary variable of interest for the purpose of calculation of sample size was NT-proBN P values as reported in study by Davoodi et al. They reported the SD of 838.51 among responders and 485.96 among nonresponders. These values were substituted in following formula.
Z1-α-/2 = 1.96 = 5% level of significance.
Z1-β =0.84 = Power.
d = minimum medically difference to be detected.
We considered d = 350 on the minimum medically relevant difference for detection with power 80%. At significance level of 5%, the sample size comes to 60.
Method of measurement of outcome of interest
The outcome variables NT-proBNP, echocardiography, QRS duration in ECG, and evaluation of patients on the basis of history, examination and 6 min walk test pre- and post-CRT was done and all the measures was taken to avoid the bias with periodical noting at 3 and 6 months.
Blood sampling and N-terminal pro B-type natriuretic peptide assay
Blood sampling was performed at 8 a.m. before and 3 and 6 months after implantation following rest in supine position. NT-proBNP Johnson and Johnson autoanalyzer was utilized for measuring NT-proBNP. The results were depicted in pg/ml.
Trans-thoracic two-dimensional and continuous-wave Doppler with color-flow imaging echocardiographic studies was conducted with a commercially available ultrasonographic system (TTE Philips IE 33, Philips Andover, Andover, USA). The left ventricular dimensions, left ventricular end systolic volume (LVESV), and left ventricular end diastolic volume (LVEDV) were measured according to the guidelines of the American Society of Echocardiography. In addition, the LVEF was evaluated with the modified Simpson method. Mitral regurgitation was diagnosed by color Doppler and quantified using a semi-quantitative scale of 1-4.
Six minutes' walk test
Six minutes' walk test was done as per the American Thoracic Society Guideline 2002.
Descriptive variables were used for all variables. Continuous variables were expressed as mean ± Standard deviation or mean ± SEM when specified. The student “t“-test was used to compare the continuous variable. Chi-square or Fisher's Exact test was used to find association between categorical variables. The differences in the NT-proBNP level (pg/ml) pre and post CRT across the duration of study was determined through ANOVA. SPSS version 20.0 (IBM Inc., New York, USA) was used for all the statistical analysis, with statistical significance set at P ≤ 0.05.
| Results|| |
A total of 60 HF patients with NYHA Class III (88%) and ambulatory class IV (12%) with available NT-proBNP circulating levels at baseline were evaluated and followed up at 3 and 6 months. The mean age of the patients was 62 years, 39 (65%) of whom were males and 21 (35%) were females. HF etiology having dilated cardiomyopathy comprised of 41 (68.3%) patient while ischemic cardiomyopathy had 19 (31.6%) patient. Fifty-one (85%) patients had LBBB pattern in baseline ECG with mean QRS duration of 147.5 ms ± 16.6.
Baseline echocardiography showed a severe systolic dysfunction with a mean LVEF of 26.8% and severe LV dilation (LVESV and LVEDV, 132.3 ml and 179.4 ml, respectively). Totally, 44 patients (73%) had mild MR, while 16 patients (27%) had moderate to severe MR. The most common symptoms were exercise intolerance reported in 52 patients (86.6%) followed by orthopnea in 51 (85%) and history of ankle edema in 50 (83%) patients. A systolic murmur was observed in 30 patients (50%) followed by chest crepitations and rhonchi in 28 (46.6%) and 21 (35%) patients, respectively. Patients covered on average 276.8 m ± 58.92 in the 6-min walk test.
Laboratory tests showed a mean creatinine of 1.04 mg/dl, mean hemoglobin of 12.9 mmol/L, and mean NT-proBNP 4200.8 pg/ml. Medical treatment included loop diuretics (100%), β-blockers (85%), angiotensin converter-enzyme inhibitors or angiotensin II receptor blockers (96%), potassium sparing diuretics (91.6%), digoxin (75%), and antiarrhythmic drugs (18.3%) [Table 1].
Clinical, echocardiographic, and neurohormonal response to cardiac resynchronization therapy
At 3 months' follow-up, significant improvements in NYHA functional class (from 3.11 ± 0.32 to 2.65 ± 0.52, P = 0.007), 6-min walked distance (from 276.8 m ± 58.9 to 322.4 m ± 78.6, P = 0.01) were demonstrated in the overall population. Improvement in dyspnea occurred by at least one NYHA class (average 0.73) in most of the patients after 6 months. 6MWT showed increase in average distance travelled by 45 meter at 3 months and 81 meter at 6 months. The mean QRS width decreased significantly after biventricular (BiV) pacing (147.53 ms ± 16.6 at baseline vs. 128.0 ms ± 12.35 at 3 months P = 0.01) with the difference became more significant after 6 months (P = 0.01) [Figure 1].
|Figure 1: Graphic representation of QRS duration, NYHA class, 6MWT, and NT.proBNP at baseline and at 3 and 6 months|
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Finally, a significant reduction in NT-proBNP levels was observed (from 4200.8 pg/ml ± 1285.2 at baseline to 3187.0 pg/ml ± 1786.72 at 3 months and 2515 pg/ml ± 2321.97 at 6 months) (P = 0.0001).
The repeat echocardiogram at 3 months' follow-up showed a significant reduction in LV volumes (LVESV: from 132.3 ml to 120.6 ml, P = 0.02); LVEDV: from 179.4 ml to 168.0 ml, P = 0.023) with a significant improvement in LVEF (from 26.8% to 29.2%, P = 0.008). No significant reduction in LV diameters (LV end-systolic diameter: from 48.7 to 47.3 mm, P = 0.38; and LV end diastolic diameter: from 58.1 to 58.1 mm, P = 1.00) were observed over 3 months' follow-up. There was also a non-significant reduction in the severity of mitral regurgitation with 11 patients (18.3%) showing moderate-to-severe MR at 3 months compared to 16 patients (27%) at baseline (P = 0.1).
At 6 months' follow-up reduction in LV volumes and LVEF became more significant compared to baseline. There were further reduction in LV diameters also [LV end systolic diameters decreased from 48.7 mm at baseline to 45.4 mm at 6 month (P = 0.065) and LV end diastolic diameters decreased from 58.1 mm at baseline to 57.1 mm at 6 month (P = 0.519)], but no statistical significant difference could be observed.
Finally, significant reduction in severity of mitral regurgitation was observed with only 8 (13.3%) patients showing moderate-to-severe MR at 6 month compared to 16 patients (27%) at baseline (P = 0.001) [Table 2].
|Table 2: Comparison of echocardiographic variables before and after cardiac resynchronization therapy|
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If we consider, ≥15% LVESV reduction as echocardiographic responders to CRT as observed in various studies, a total of 45 patients (75%) showed ≥15% LVESV reduction. When a definition of CRT response of ≥15% reduction in NT-proBNP levels was applied, then also 45 patients (75%) were classified as responder showing concordance between echocardiographic and NT-proBNP definitions of CRT response.
In order to evaluate whether the changes in neurohormonal status after CRT implantation reflects the clinical response to CRT, the concordance between clinical and NT-proBNP definition of response to CRT was assessed. At 6 months' follow-up, 75% of patients (n = 45 of 60) showing clinical response (evaluated in previous studies as improvement in NYHA class) also showed NT-proBNP response. In contrast, 25% of patients (n = 15 of 60) without a clinical improvement did not show a reduction in circulating levels of NT-proBNP. A good association between neurohormonal response and clinical response to CRT was demonstrated; odds ratio 1.00 (95% confidence interval = 0.43–2.28). The baseline clinical characteristics and medications of responders and nonresponders are shown in [Table 3]. There was no significant difference between the responders and nonresponders with respect to age, gender, HF etiology and NYHA functional class before CRT. Only statistical significant difference was observed in QRS widening at baseline between responders and nonresponders (P < 0.05). In addition, no significant difference was found in terms of medications between the two groups.
|Table 3: Baseline characteristics of the study group, the responders and nonresponders|
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The comparisons of the clinical, echocardiographic and neurohormonal characteristics at baseline versus 6 months' follow-up and the responders versus non-responders are presented in [Table 4].
|Table 4: Comparison of clinical, echocardiographic, and neurohormonal data at baseline and 6 months after cardiac resynchronization therapy in responders versus nonresponder|
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Significant change in NYHA class at 6 months was observed in responders compared to nonresponders. The QRS duration amongst the responders had a significant reduction at 6 months. In addition, a comparison between the 6-minute walk test results of the two groups of patients before and 6 months after implantation showed a significant improvement in responders [Table 4].
At baseline, statistically significant difference in LVESV was observed between responders and non-responders (P < 0.05). Change in LVESV and LVEDV were also found to be significant in the responders after 6 months. In addition, the change in LVEF was significant after 6 months in the patients who had responded to CRT compared to nonresponders, although there was no baseline difference in LVEF between responders and nonresponders. The changes in the LV diameters, albeit in the anticipated directions, were not statistically significant during the follow-up.
At baseline, plasma level of NT-proBNP was 3792.3 pg/ml ± 939.2 in responders compared to 5426.1 pg/ml ± 1359.6 in non-responders, which was highly significant [Table 4]. At 6 months' follow-up, the change in NT-pro BNP between pre-CRT and 6 months' post-CRT evaluations was significantly more important in responders than in nonresponders (absolute: −2531.31 pg/ml ± 880.54 vs. 852.2 pg/ml ± 1055; P < 0.001).
| Discussion|| |
The present study shows the clinical benefit of treating patients with CRT. It also points to the reverse ventricular remodeling that occurs with this therapy, with a progressive and sustained decrease in LV volumes, increase in LVEF, and decrease of the severity of mitral valve regurgitation. Such increases in LVEF were also substantial in the MIRACLE study and in other trials after treatment with CRT.,
The key finding of our research was that CRT induced a substantial reduction in NT-proBNP plasma levels in responders, with no significant change in non-responders after 3 and 6 months of follow-up. Such improvements in NT-proBNP levels between baseline and 3 and 6 months after CRT could be useful in identifying echocardiographic responders.
The analysis of the data in the present study showed that baseline NT-proBNP in non-responder group was significantly higher than in previous studies, where there was no significant difference in NT-proBNP between responders and non-responders., Similar to our finding, Davoodi et al. also noted that NT-proBNP increased marginally or remained unchanged in nonresponders compared to those of responders where there was a substantial decline. Significant difference in NT-proBNP between responders and non-responders was observed both at 3 and 6 months by Zoltan et al., where reduction in NT-proBNP was of similar magnitude for clinical or echo responders. Mortada et al. noted significant reductions (P < 0.05) in plasma BNP levels from baseline to 3-month follow-up in 87% of their study participants. Sinha et al. in 2003 documented significant reductions in BNP levels associated with significant reductions in LV volume and a significant increase in ejection fraction, which remained consistent throughout long-term follow-up (>1 year) in patients treated with BiV pacing. Moreover, the CARE-HF post hoc analysis also concluded that BNP may be used to monitor CRT effect.
CRT response is clearly a multifactorial process including the severity of intraventricular asynchrony, presence and localization of LV viability and lead placement with respect to the latest LV activation site. In contrast, BNP or NT-proBNP release is essentially determined by LV wall stress. Hence, it is not surprising that in some studies baseline NT-proBNP failed to predict the clinical or echocardiographic response after CRT.
Our study also documented improvement in clinical parameters (reduction in NYHA class and improvement in 6 min walk test) in CRT responders compared to nonresponders which was in co-relation with NT-proBNP response. NYHA class was decreased by at least one level after 6 months in responders compared to non-responders similar to previous studies.,
The difference in QRS duration between responders and non-responders was another important finding of this study. Baseline QRS duration was significantly higher in responders, compared to non-responders (P = 0.0293) which was in contrast to studies reported by Davoodi et al. and Nawar et al., where there was no significant difference between these two groups. However, our study was in accordance with Bristow et al., where CRT response seems to increase as the QRS duration becomes longer, with greatest benefit in those with a QRS duration ≥150 ms.
Our investigation also supports the efficacy of CRT on the improvement of LVEF in patients with HF. Furthermore, our results showed that NT-proBNP is also a good surrogate marker to identify LV remodeling following CRT. Since LV remodeling predicts outcome with better accuracy than clinical improvement after CRT and that BNP monitoring can identify echocardiographic responders with a very good sensitivity and specificity, assessment of BNP after CRT could be used as an additional tool to assist the clinician in the evaluation of the patient's condition. The long-term outcome of CRT could be predicted by changes in NT-proBNP level earlier after implant of the CRT system (i.e., after 3 months). This is supported by the fact that patients at high risk of HF should be followed more closely and receives more aggressive clinical management, including programming of timing intervals and basic heart rate, fine tuning pacing mode and more aggressive therapeutic strategies.
One important finding of this study is that LV remodeling can be identified by change in neurohormone level early (3–6 months) after CRT. Patients identified as nonresponders may be followed more closely. Previous studies use different definitions of CRT response varying from functional parameters (such as NYHA class, 6 min walking test) to reverse LV remodeling and/or toward morbidity and mortality. The property of BNP to define the CRT response is related to the fact that the peptide reflects the complex functional and anatomical status of the cardiovascular system as a whole and may therefore be a more sensitive parameter of clinical status.
| Conclusion|| |
In our study, individuals without LV reverse remodeling had a higher concentration of NT-proBNP initially and after the given follow-up period, NT-proBNP decreased only in patients with reverse remodeling. This suggests that LV reverse remodeling is associated with an improvement in the biochemical parameters of CHF.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]