Overall, the plasma BNP levels seem to reflect the pump speed settings of LVAD. The correlation was statistically significant for the entire group (Supplemental digital content, Table 1 at http://links.lww.com/ASAIO/A3) and individual patients while BNP levels were investigated in different pump speeds (see Supplemental Digital content, Figure 1 at http://links.lww.com/ASAIO/A1 and Figure 2 at http://links.lww.com/ASAIO/A2). The serum creatinine levels also reflected the various pump speed settings, but the correlation was not as significant as that of BNP.
B-type natriuretic peptide levels after a change in RPM (without including other pertinent data that might affect BNP levels such as transfusion, dialysis, inotropic medication use, or existence of RV failure) were analyzed. B-type natriuretic peptide values were significantly less than before at first 2 days after RPM increase (prechange BNP, 1,420 ± 1,125 pg/ml; postchange day 1, 1,168 ± 918 pg/ml; postchange day 2, 912 ± 599 pg/ml; p = 0.028). Significant increase of BNP was only observed the following first day when RPM was decreased (p = 0.008) but not after (prechange BNP, 1,046 ± 927 pg/ml; postchange day 1, 1,471 ± 1,177 pg/ml; postchange day 2, 1,153 ± 930 pg/ml; p = 0.13).
In the BTT group involving nine patients, four underwent cardiac transplantation. Two patients, who were weaned from LVAD successfully after the myocardial recovery, had a rapid reduction of their BNP values during their postoperative period. The values were reduced to <200 pg/ml 1 month after LVAD implantation. The patient with postpartum cardiomyopathy was successfully weaned after 4 months of VAD support. The other patient with dilated cardiomyopathy developed a device failure due to a broken driveline. His device was defunctionalized because his heart was recovered. One patient who had been supported on LVAD for a year died suddenly at home. The remaining patients are still awaiting heart transplantation on LVAD support.
There were two late deaths in the DT group. One died from an iatrogenic noncardiac cause whereas the other died from a hemorrhagic stroke after cerebral embolism.
The BNP is a well-studied biological marker in patients with heart failure.8,9 It is well known that a higher level of BNP is associated with a worse prognosis in patients with advanced heart failure. However, the natural history and the physiology of patients with advanced heart failure can be altered greatly with LVAD therapy. After implantation of an LVAD, the LV is unloaded and the cardiac output improves immediately.10 During this period of rapid hemodynamic change, we followed serial BNP levels to see whether they would reflect the physiological improvement associated with a successful VAD support. The highly elevated preoperative BNP levels decreased steadily over the next 3 months, provided there were no problems with hemodynamic support rendered by LVAD. When patients encountered the situations of inadequate circulatory support because of problems such as acute LVAD failure, thrombus on impeller, tamponade, and/or profound RV dysfunction, their BNP levels increased noticeably. Then, it was reassuring again to witness the return of the decreasing trend of BNP levels following the corrective measures to address the problems that contributed to the inadequate circulatory support.
The need to follow a physiological marker such as BNP is more compelling in the era of continuous-flow LVADs. The earlier LVADs were based on the volume displacement technology and provided given stroke volumes and rates similar to the native heart. The usual clinical parameters such as blood pressures and pump rates could be followed to assess a patient's condition. However, with the newer generation LVADs, the blood is propelled in a continuous manner. Patients lack palpable pulse rates and pressures but only pulses measurable by Doppler. Following the trend of normalization of values of a physiological marker such as BNP may assure clinicians that LVAD support is adequate in providing forward flow and unloading of the LV. Furthermore, BNP levels may serve as a helpful physiological feedback parameter in adjusting the pump speed for an optimal setting in each patient. For example, a higher pump speed would be needed in patients with systemic hypertension or with an aortic insufficiency to compensate for a regurgitant flow. Although the echocardiography would be very helpful in understanding the degree of LV unloading, it makes no inference to the physiological impact of such unloading. It would be reassuring to clinicians to witness normalization of BNP levels in these patients.
The half-life of BNP in the circulation is quite short, with a mean length of 20 minutes. B-type natriuretic peptide accurately reflects current ventricular status. Generally, a BNP concentration <100 pg/ml would make the diagnosis of heart failure unlikely. There is a diagnostic “gray area,” often defined as between 100 and 500 pg/ml, for which the test is considered inconclusive.11,12 Values >500 pg/ml are generally considered to be positive in CHF. Few data are available on serial measurements of BNP in advanced chronic heart failure. In the Valsartan Heart Failure Trial (ValHeFT), those patients with the greatest reduction in their BNP concentration had the lowest mortality over the course of the study.13 We observed similarly uneventful hospital course and shorter hospital stay in our patients whose BNP levels lowered <500 pg/ml in couple of weeks after LVAD therapy.
There are several interventions or clinical conditions that may have occurred simultaneously with the modification of the device speed such as adjusting medical therapy (i.e., diuretics, neurohormonal blockade, and right ventricular dysfunction) that could have a similar effect on BNP. To lessen the degree of these confounders, we analyzed BNP levels just after RPM change (different time points between patients) and observed how quickly and effectively levels were decreased after RPM is increased. These were more prominent in 2 days after change. The similar magnitude of change was only observed first day when RPM was decreased. We thought that the need for increase in RPM was related to well being in hemodynamics, echocardiographic findings of LV filling, or aortic valve opening, which all will be reflected as a decrease in BNP by better LV unloading. On contrary, a need for RPM decrement would be a suction effect and/or septal shifting causing RV failure, which all may reflect as BNP decrease with better hemodynamics re-established even when speed is lowered.
The correlation of BNP with RPM was statistically apparent with the HeartMate II but not Jarvik 2000. Various factors such as a wider range of adjustable RPM, a more effective unloading of the LV, and a more complete hemodynamic support with the Heartmate II over Jarvik 2000 might have yielded the better correlation with BNP. We also encountered more episodes of troublesome hemodynamic support and pump failures with Jarvik 2000. This might have contributed to the less tight correlation between BNP and RPM in patients with Jarvik 2000.
The continuous-flow physiology created with LVAD support seems to be well tolerated clinically. Yet, our understanding is poor in this new physiology as to what constitutes the optimal LVAD support setting. How much unloading of the LV is ideal? What are the appropriate mean blood and pulse pressures? What guides us in setting the RPM? Adjusting the RPM of continuous LVAD based on a physiological feedback biomarker such as BNP might be helpful in managing these patients with this entirely new physiology. Clearly, we are facing a growing number of patients supported on continuous-flow LVAD, and we must be eager to learn this new uncharted physiology and its implication for our patients.
The limitations include those inherent to an observational study. We had a different variety of patients in etiology of heart failure, including ischemic cardiomyopathy, which reported to have weak release of BNP due to necrosis and myocardial stiffness. Nevertheless, we observed satisfactory post-LVAD BNP decrease in this etiology.
Furthermore, there are several clinical conditions that may have occurred simultaneously with the modification of the device speed such as adjusting medical therapy (i.e., diuretics, dialysis, transfusions, and neurohormonal blockade right ventricular dysfunction) that could have a similar effect on BNP. All those confounders' magnitude in BNP for each patient for a given time is difficult to estimate. Addition to that one level of RPM may mean a different level of support and unloading between patients reflecting different BNP levels. We investigated each patient separately grouping altered speed levels in each other in different time points trying to minimize effect of such confounders. Also, whenever a change was present in RPM, BNP levels were analyzed, which might lessen the effect of these confounders.
Patients with no alteration with RPM or patients with less alteration duration at that RPM level generated none or very few BNP levels to perform sufficient correlation analysis. Related to prospective nature of the study, neither of these patients, other than clinical indications of primary responsible service, got alterations with RPM to increase the power of this study to have more correlation. Three patients with no alteration of RPM were included only in overall BNP level follow- up and correlation of BNP with creatinine but not in correlation of BNP with RPM. Including larger numbers of study patients or investigating with alternating RPM in animal studies may provide powerful statistical analysis to support results of this study.
There is a relationship between adjustable speed of continuous-flow LVAD and BNP levels especially in patients who had a stable clinical course after LVAD implantation. Serial BNP measurements are helpful to monitor and optimize left ventricular unloading on axial-flow pump support.
1. Mäntymaa P, Vuolteenaho O, Marttila M, Ruskoaho H: Atrial stretch induces rapid increase in brain natriuretic peptide but not in atrial natriuretic peptide gene expression in vitro. Endocrinology
133: 1470–1473, 1993.
2. Levin ER, Gardner DG, Samson WK: Natriuretic peptides. N Engl J Med
339: 321–328, 1998.
3. Yasue H, Yoshimura M, Sumida H, et al
: Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation
90: 195-203, 1994.
4. Sodian R, Loebe M, Schmitt C, et al
: Decreased plasma concentration of brain natriuretic peptide as a potential indicator of cardiac recovery in patients supported by mechanical circulatory assist systems. J Am Coll Cardiol
38: 1942–1949, 2001.
5. Xydas S, Rosen RS, Ng C, et al
: Mechanical unloading leads to echocardiographic, electrocardiographic, neurohormonal, and histologic recovery. J Heart Lung Transplant
25: 7-15, 2006.
6. Loebe M, Muller J, Hetzer R: Ventricular assistance for recovery of cardiac failure. Curr Opin Cardiol
14: 234–248, 1999.
7. Khan T, Delgado RM, Radovancevic B, et al
: Dobutamine stress echocardiography predicts myocardial improvement in patients supported by left ventricular assist devices (LVADs): Hemodynamic and histologic evidence of improvement before LVAD explantation. J Heart Lung Transplant
22: 137–146, 2003.
8. Potapov EV, Hennig F, Wagner FD, et al
: Natriuretic peptides and E-selectin as predictors of acute deterioration in patients with inotrope-dependent heart failure. Eur J Cardiothorac Surg
27: 899–905, 2005.
9. Troughton RW, Prior DL, Pereira JJ, et al
: Plasma B-type natriuretic peptide levels in systolic heart failure: Importance of left ventricular diastolic function and right ventricular systolic function. J Am Coll Cardiol
43: 416–422, 2004.
10. Madigan JD, Barbone A, Choudhri AF, et al
: Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device. J Thorac Cardiovasc Surg
121: 902–908, 2001.
11. Strunk A, Bhalla V, Clopton P, et al
: Impact of the history of congestive heart failure on the utility of B-type natriuretic peptide in the emergency diagnosis of heart failure: Results from the Breathing Not Properly Multinational Study. Am J Med
119: 69.e1–69.e11, 2006.
12. Brenden CK, Hollander JE, Guss D, et al
: Gray zone BNP levels in heart failure patients in the emergency department: Results from the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) multicenter study. Am Heart J
151: 1006–1011, 2006.
13. Anand IS, Fisher LD, Chiang YT, et al
: Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation
107: 1278–1283, 2003.
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