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244327
The latest version is at http://hwmaint.clinchem.org/cgi/doi/10.1373/clinchem.2015.244327
Clinical Chemistry 61:12
000 000 (2015)
BACKGROUND: The signal peptide for human B-type natriuretic peptide preprohormone (BNPsp), which is released from cardiomyocytes, is increased in plasma of
patients with acute myocardial infarction (AMI); however, its exact release kinetics have not been defined.
METHODS: We measured BNPsp and high-sensitivity
cardiac troponin T (hs-cTnT) in a reference group of
individuals without structural heart disease (n 285)
and determined the release kinetics of these biomarkers
in patients (n 29) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure allowing exact timing of onset of iatrogenic AMI. Blood samples were
collected before TASH and at numerous preselected time
points after TASH.
RESULTS: The reference median BNPsp concentration
was 53.4 pmol/L [interquartile range (IQR) 47.0 61.0;
95th percentile 85.9 pmol/L; 99th percentile 116.3
pmol/L]. Baseline concentrations in patients undergoing
TASH were higher than in the reference group [91.9
pmol/L (IQR 62.9 116.4); P 0.0001]. BNPsp increased significantly, peaking at 15 min after induction of
AMI [149.6 pmol/L (109.5204.9) vs baseline; P
0.004] and declining slowly thereafter, falling below the
preprocedural value after 8 h (P 0.014). hs-cTnT increased significantly 15 min after induction of AMI [26
ng/L (19 39) vs 18 ng/L (1129); P 0.001] and remained high at all later time points.
CONCLUSIONS: BNPsp concentrations increased immediately after AMI induction, providing early evidence of
myocardial injury. The release kinetics of BNPsp differed
Department of Cardiology, Kerckhoff Heart and Thorax Center, Bad Nauheim, Germany;
DZHK (German Centre for Cardiovascular Research), partner site RheinMain, Frankfurt
am Main, Germany; 3 Department of Internal Medicine I, Division of Cardiology, University of Giessen, Giessen, Germany; 4 Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, New Zealand; 5 Cardiovascular Research Institute, National University of Singapore, Singapore.
* Address correspondence to this author at: Kerckhoff Heart and Thorax Center, Department of Cardiology, Benekestr. 2-8, 61231 Bad Nauheim, Germany. Fax +49-6032-9962361; e-mail c.liebetrau@kerckhoff-klinik.de.
Received June 5, 2015; accepted September 22, 2015.
2
from those of hs-cTnT. These findings provide information that should help in establishing the diagnostic value
of BNPsp in the setting of early AMI.
2015 American Association for Clinical Chemistry
Another group of 29 patients with hypertrophic obstructive cardiomyopathy (HOCM) who were scheduled for
TASH from January 2010 to January 2014 were included in the study. Pre- and postprocedural management as well as the proof of concept of the TASH method
as an equivalent for AMI have been recently published
(1317 ). In brief, a clinical history and the results of a
physical examination, 12-lead electrocardiography, laboratory tests, echocardiography, and coronary angiography were assessed for all patients. The final diagnosis of
HOCM was made according to the current guidelines on
the basis of severe symptoms during physical activity,
asymmetrical septal hypertrophy 15 mm, systolic
movement of the anterior mitral valve leaflet, and an
intraventricular pressure gradient of 30 mmHg at rest
and/or 50 mmHg after provocation by the Valsalva
maneuver (18 ). All patients received analgesic and anxiolytic pretreatment. Patients were free of renal or liver
dysfunction and had healthy blood values. TASH was
performed according to standard clinical practice with
temporary septal branch occlusion for selective therapeutic injection of 96% ethanol. All TASH procedures were
BNPsp was measured at the Christchurch Heart Institute, New Zealand, via specific immunoassay as previously described (10 ) with a methodological change in
sample processing before assay. The samples were airshipped on dry ice within 36 h without thawing. To
maximize recovery and reduce nonspecific interactions,
plasma samples were mixed with an equal volume of 0.1
mL HCl and centrifuged to remove high molecular
weight protein debris before extraction on Sep-Pak C18
cartridges. This method modification improved recovery
of synthetic and endogenous BNPsp from 74% to 90%
and stabilized resulting assay samples through reduced
protein interference. Because of the improved recoveries,
a new reference group was required to establish appropriate healthy range and 99th percentile values, as reported
here.
hs-cTnT MEASUREMENTS
Table 1. Baseline characteristics of the reference group without coronary artery disease, hs-cTnT concentrations <14 ng/L (99th
percentile), and NT-proBNP concentrations <300 ng/L.a
Variable
Reference group
285
Age, years
58.9 (11.1)
Male
117 (41.1)
29.0 (5.4)
220
65
55.9 (9.8)
68.6 (9.7)
94 (42.7)
28.7 (5.2)
23 (35.4)
30.1 (6.0)
<0.0001
0.32
0.12
81 (36.8)
16 (24.6)
0.075
Hypertension
Current smoking
197 (69.1)
144 (65.5)
53 (81.5)
0.014
Hypercholesterolemia
162 (56.8)
126 (57.3)
36 (55.4)
0.89
Diabetes mellitus
30 (10.5)
24 (10.9)
6 (9.2)
0.82
Family history
92 (32.3)
74 (33.6)
18 (27.7)
0.45
Beta-blockers
133 (46.7)
100 (45.5)
33 (50.8)
0.48
ACE inhibitors
139 (48.8)
95 (43.2)
44 (67.7)
0.001
68 (23.9)
58 (26.4)
10 (15.4)
0.07
4 (6.2)
0.05
Medication
Statins
Aldosterone receptor antagonists
Heart rate, bpm
7 (2.5)
3 (1.4)
67.8 (11.7)
66.7 (11.5)
71.5 (11.9)
0.004
135.5 (18.9)
133.1 (17.9)
143.3 (20.3)
<0.0001
78.2 (10.5)
77.9 (10.6)
78.9 (10.0)
0.29
60.2 (3.6)
60.3 (3.8)
59.9 (2.9)
0.59
BNPsp, pmol/L
53.4 (47.061.0)
52.0 (46.659.5)
56.4 (49.669.8)
0.003
90th percentile
76.2
73.9
85.5
95th percentile
85.9
84.3
100.9
97.5th percentile
91.5
88.9
125.6
Laboratory measurements
99th percentile
116.3
hs-cTnT, ng/L
<3 (<3)
<0.0001
81.6 (40.4145.5)
81.6 (39.6141.4)
82.1 (45.2158.4)
0.58
Creatinine, mg/dL
0.73 (0.610.84)
0.71 (0.610.83)
0.81 (0.650.91)
0.012
100.3 (86.9116.3)
103.5 (90.1117.6)
GFR, mL min
(1.73 m )
2 1
91.8 (26.9)
<0.0001
Data are mean (SD), n (%), or median (IQR). To convert creatinine values from mg/mL to mol/L, multiply by 88.4.
0
6 (59)
NT-proBNP, ng/L
1
92.1
<3 (<3)
Age, years
Value
60.4 (13.4)
Male
13 (44.8)
30.7 (6.0)
10 (34.5)
Hypertension
17 (58.6)
Hypercholesterolemia
11 (37.9)
Diabetes mellitus
6 (20.7)
Family history
7 (24.1)
Medication
Fig. 2. Distribution pattern of BNPsp concentrations in individuals without coronary artery disease and hs-cTnT concentrations <99th percentile (14 ng/L).
Beta-blockers
11 (37.9)
ACE inhibitors
12 (41.4)
Statins
10 (34.5)
Aldosterone receptor
antagonists
18 (62.1)
29 (100)
Laboratory measurements
Creatinine, mg/dL
GFR, mL min1 (1.73 m2)1
NT-proBNP, ng/L
0.88 (0.771.03)
90.53 (79.04113.73)
1001.0 (486.81949.5)
Data are mean (SD), n (%), or median (IQR). To convert creatinine values from mg/dL
to mol/L, multiply by 88.4.
Fig. 3. Plasma concentrations of BNPsp and serum concentrations of hs-cTnT [median (IQR)] in patients undergoing
TASH at baseline and throughout the study.
Light gray bars, hs-cTnT; dark gray bars, BNPsp; light gray line,
hs-cTnTspecic 99th percentile (14 ng/L); dark gray line, BNPspspecic 99th percentile (92.1 pmol/L); circles, outlier data points;
asterisks, rst time point with signicant increase (P < 0.01) compared with baseline.
Baseline
15 min
Median (IQR)
hs-cTnT, ng/L
Minimummaximum
Median (IQR)
Minimummaximum
91.9 (62.9116.4)
43.3270.5
18 (1129)
<354
149.6 (109.5204.9)
78.6384.6
26 (1939)
1198
30 min
135.4 (105.7180.7)
62.0316.9
51 (3372)
18363
45 min
130.2 (98.6158.9)
59.3298.5
83 (68112)
28450
60 min
131.1 (88.5150.5)
60.6380.6
118 (80174)
36712
75 min
123.5 (85.1154.3)
63.8224.6
149 (109217)
49832
90 min
112.2 (81.8155.2)
63.3235.5
197 (126309)
62964
105 min
112.3 (93.2149.0)
64.6263.7
234 (154324)
93933
2h
109.1 (79.9130.9)
67.4300.2
284 (172508)
1061183
4h
81.2 (65.3102.6)
50.8274.4
553 (360861)
1281936
8h
60.9 (50.086.2)
39.1176.3
974 (7511640)
2643359
24 h
48.6 (42.356.1)
38.167.6
2239 (16392571)
6334818
but because of the low number of patients, this correlation was not significant.
Nevertheless, our data show that there is a rapid and
robust release of BNPsp within the first 15 min after
induction of myocardial infarction; subsequently, concentrations decrease and return to levels comparable to
those of the reference population after 24 h, possibly
from a reduction in myocardial wall stress. We observed
a correlation between concentrations of hs-cTnT and
BNPsp in the reference population; however, there was a
significant difference in the release kinetics of the 2 biomarkers after TASH. Whereas hs-cTnT concentrations
increased continuously throughout the observation window, BNPsp concentrations peaked within 15 min and
then decreased to baseline levels or lower within 8 h after
TASH. This rapidly rising and falling (i.e., dynamic)
profile is consistent with our previous observations in
ST-segment elevation myocardial infarction patients
(10 ) and in those undergoing dobutamine stress echo
testing (26 ). The early rise after induction of AMI is also
in accordance with previous data describing the release of
NT-proBNP after TASH (15 ). Nevertheless, BNPsp
seems to have a shorter half-life than NT-proBNP and
might be more comparable to the release and half-life of
BNP. There are no reports of data showing the exact
release kinetics of BNP.
Understanding the time course of the release of
cTnT and BNPsp and correlating the concentrations
with patient symptoms and the results of electrocardiogram and imaging studies is important for early diagnosis, individual risk stratification, and individualized therapy, especially in the hours soon after symptom onset.
Measurement of BNPsp could be helpful in diagnosing
or excluding AMI in early presenters, as has been shown
for other biomarkers (6, 8 ), and may offer increased
specificity for AMI when combined with high-sensitivity
troponin assay results. Measurement of both cTnT and
BNPsp concentrations might assist in estimating the time
of onset of an AMI: high BNPsp and low cTnT concentration would indicate very recent onset, whereas low
BNPsp and high cTnT concentration might reflect an
AMI several hours into its evolution. This hypothesis
needs to be tested in a patient cohort with suspected
AMI.
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