Boomsma, Frans

Deinum, J (Jacob)

van den Meiracker, Ton

English

EUR Research Repository

injury (13 ). In patients with severe chronic heart failure(NYHA III and NYHA IV), cTnI (4, 6) and cTnT (5, 7) areoften increased. In our study, none of three carriers withan increased CK-MB/CK-total ratio had dilated cardio-myopathy and none had detectable troponins. Thus aCK-MB/CK-total ratio .3% did not appear to be indica-tive of severe cardiac abnormalities in our study popula-tion. Two carriers had detectable cTnT; in one carrier withborderline echocardiographic abnormalities, it wasslightly increased. In all other carriers, cTnT was notdetectable. None of the carriers had detectable cTnI.Although 30 women (23%) among the DMD/BMD carri-ers showed left ventricle dilation or dilated cardiomyop-athy on echocardiography, these abnormalities probablyreflected cardiac dysfunction rather than cardiac cellnecrosis. In our study group, no carrier had severe heartfailure that was associated with increased troponins. cTnIand cTnT can be used, however, for carriers suspected ofcardiac ischemia. Measurement of CK-MB alone couldgive a false-positive result because of high total CK.Some authors have found a negative correlation be-tween CK activity and age in DMD (14 ) and BMD carriers(15 ), whereas others have not (16 ). We found no suchcorrelation, but we were able to demonstrate a linearlydecreasing trend of total CK with increasing age groups ofcarriers. Surprisingly, only 53% of DMD carriers and 30%of BMD carriers had increased total CK. Only one earlierstudy found similar percentages (17 ), whereas most otherstudies found raised CK activity in 60–80% in DMD(16, 18–22) and 42–62% of BMD carriers (15, 20, 22).These relatively high percentages prompted clinicians inthe predystrophin era to calculate the risk of being acarrier. Perhaps the difference between our study andthose carried out before the 1990s is that in most of theseinvestigations, repeat measurements of total CK weredone, whereas we performed only one measurement.In conclusion, detectable cTnI and cTnT are rare inDMB and BMD carriers and bear no relationship withdisease-specific cardiac abnormalities. We cannot excludethe possibility that cTnI and cTnT will be increased incarriers with severe heart failure because no severe heartfailure was present in our study group.References1. Larue C, Calzolari C, Bertinchant JP, Leclercq F, Grolleau R, Pau B.Cardiac-specific immunoenzymometric assay of troponin I in the early phaseof acute myocardial infarction. Clin Chem 1993;39:972–9.2. Katus HA, Remppis A, Neumann FJ, Scheffold T, Diederich KW, Vinar G, etal. Diagnostic efficiency of troponin T measurements in acute myocardialinfarction. Circulation 1991;83:902–12.3. Bodor GS, Porter S, Landt Y, Ladenson JH. Development of monoclonalantibodies for an assay of cardiac troponin-I and preliminary results insuspected cases of myocardial infarction. Clin Chem 1992;38:2203–14.4. La Vecchia L, Mezzena G, Zanolla L, Paccanaro M, Varotto L, Bonanno C,Ometto R. Cardiac troponin I as diagnostic and prognostic marker in severeheart failure. J Heart Lung Transplant 2000;19:644–52.5. Setsuta K, Seino Y, Takahashi N, Ogawa T, Sasaki K, Harada A, et al. Clinicalsignificance of elevated levels of cardiac troponin T in patients with chronicheart failure. Am J Cardiol 1999;84:608–11.6. Missov E, Calzolari C, Pau B. Circulating cardiac troponin I in severecongestive heart failure. Circulation 1997;96:2953–8.7. Missov E, Mair J. A novel biochemical approach to congestive heart failure:cardiac troponin T. Am Heart J 1999;138:95–9.8. Hoogerwaard EM, van der Wouw PA, Wilde AAM, Bakker E, Ippel PF,Oosterwijk JC, et al. Cardiac involvement in carriers of Duchenne and Beckermuscular dystrophy. Neuromuscul Disord 1999;9:347–51.9. Hoogerwaard EM, Bakker E, Ippel PF, Oosterwijk JC, Majoor-Krakauer DF,Leschot NJ, et al. Signs and symptoms of Duchenne muscular dystrophy andBecker muscular dystrophy among carriers in the Netherlands: a cohortstudy. Lancet 1999;353:2116–9.10. Horder M, Elser RC, Gerhardt W, Mathieu M, Sampson EJ. Approvedrecommendation IFCC methods for measurement of catalytic concentra-tions of enzymes. Part 7. Method for Creatine Kinase. Eur J Clin Chem ClinBiochem 1991;29:435–56.11. Eyre DR, Koob TJ, Van Ness KP. Quantification of hydroxypyridiniumcrosslinks in collagen by high-performance liquid chromatography. AnalBiochem 1984;137:380–8.12. Adams JE, Bodor GS, Davila-Roman VG, Delmez JA, Apple FS, Ladenson JH,Jaffe AS. Cardiac troponin I. A marker with high specificity for cardiac injury.Circulation 1993;88:101–6.13. Missov ED, De Marco T. Clinical insights on the use of highly sensitivecardiac troponin assays. Clin Chim Acta 1999;284:175–85.14. Moser H, Vogt J. Follow-up study of serum-creatine-kinase in carriers ofDuchenne muscular dystrophy. Lancet 1974;2:661–2.15. Kingston HM, Sarfarazi M, Newcombe RG, Willis N, Harper PS. Carrierdetection in Becker muscular dystrophy using creatine kinase estimationand DNA analysis. Clin Genet 1985;27:383–91.16. Emery AEH. Duchenne muscular dystrophy, 2nd ed. New York: OxfordUniversity Press Inc, 1993:392pp.17. Nicholson GA, Gardner-Medwin D, Pennington RJ, Walton JN. Carrier detec-tion in Duchenne muscular dystrophy: assessment of the effect of age ondetection-rate with serum-creatine-kinase-activity. Lancet 1979;1:692–4.18. Falcao-Conceicao DN, Goncalves-Pimentel MM, Baptista ML, Ubatuba S.Detection of carriers of X-linked gene for Duchenne muscular dystrophy bylevels of creatine kinase and pyruvate kinase. J Neurol Sci 1983;62:171–80.19. Wilson KM, Evans KA, Carter CO. Creatine kinase levels in women who carrygenes for three types of muscular dystrophy. BMJ 1965;1:750–3.20. Zatz M, Frota-Pessoa O, Levy JA, Peres CA. Creatine-phosphokinase (CPK)activity in relatives of patients with X-linked muscular dystrophies: aBrazilian study. J Genet Hum 1976;24:153–68.21. Percy ME, Andrews DF, Thompson MW. Serum creatine kinase in thedetection of Duchenne muscular dystrophy carriers: effects of season andmultiple testing. Muscle Nerve 1982;5:58–64.22. Emery AE, Clack ER, Simon S, Taylor JL. Detection of carriers of benignX-linked muscular dystrophy. BMJ 1967;4:522–3.Relationship between Natriuretic Peptide Concentra-tions in Plasma and Posture during Blood Sampling,Frans Boomsma,* Jaap Deinum, and Anton H. van denMeiracker (Department of Internal Medicine, ErasmusUniversity Medical Center, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands; * author for correspon-dence: fax 31-0-10-4634531, e-mail boomsma@inw1.azr.nl)Measurements of the plasma concentrations of one ormore of the natriuretic peptides can be a valuable tool inthe diagnosis, prognosis, and follow-up of patients withcardiac dysfunction (1, 2). Measurement techniques havealso improved, allowing for less time-consuming directassays than previous methods, which often required theprior extraction of peptides from plasma. However, im-provement is still needed (3 ).In most research settings, blood sampling is performedunder carefully controlled conditions, involving the intro-duction of a catheter and ample bed rest before thecollection of blood. Such procedures are necessary for thereliable interpretation of many neurohormone measure-ments. Catecholamines, for example, can fluctuate widelydepending on the blood-sampling procedure and posture.Because strictly adhering to rigorous blood-sampling pro-Clinical Chemistry 47, No. 5, 2001 963tocols is often impossible in everyday clinical situations,we investigated the variation in measured natriureticpeptide concentrations because of differences in blood-sampling conditions.We have measured atrial natriuretic peptide (ANP),brain natriuretic peptide (BNP), N-terminal-pro-ANP (Nt-ANP), as well as the catecholamines noradrenaline(NOR), adrenaline, renin (REN), and aldosterone (ALDO).We studied subjects in the relevant age range (.40 years)with diseases of interest in four different blood-samplingconditions, while continuing appropriate medications forthese conditions. Twenty-three subjects (55 6 10 years;range 42–74 years) participated in the study after givingtheir informed consent. Six subjects were apparentlyhealthy controls (46 6 5 years; two females), nine werehypertensive patients (53 6 7 years; two females), andeight (64 6 9 years; three females) were patients withdiseases known to lead to increased concentrations ofnatriuretic peptides: congestive heart failure (four sub-jects) and chronic renal failure (four subjects). All patientswere taking appropriate medications for their conditions.Immediately after entering the examination room in ourdepartment, subjects sat down and a small catheter wasinserted into an antecubital vein. Blood was sampleddirectly and then after 30 min of continued quiet sitting.Blood was sampled again both after 30 min of lying on abed (bed rest) and after 30 min of standing and walking.The whole procedure was repeated on a second visit, atleast 7 days later (median interval, 12 days) to assessintraindividual variation from one day to another. Theprocedure was always performed in the morning between0900 and 1200.Blood was collected in two different tubes: (a) one tubecontaining EDTA and aprotinin (1.9 mg and 100 kIU/mLof blood, respectively) for measurement of natriureticpeptides and (b) one heparin-containing tube containing1.2 mg of glutathione/mL of blood for measurement ofNOR, adrenaline, REN, and ALDO. The tubes werecentrifuged (3000g) within 30 min at 4 °C for 10 min, andthe plasma was separated and stored at 270 °C untilassayed. ANP was determined by RIAs (Nichols Institute)after Sep-Pak C18 extraction from plasma. BNP was mea-sured with immunoradiometric assays from Shionoria,and Nt-ANP was measured with RIAs from Biotop, bothwithout extraction. Catecholamines were measured byHPLC with fluorometric detection after extraction fromplasma and derivatization with dimedone (4 ). ALDO wasdetermined with RIAs from Diagnostic Products Corpo-ration. REN was determined by RIA of generated angio-tensin I (5 ). All methods used had intraassay CVs in therelevant range of ,10%. All samples from one subjectwere measured in the same assay.Mean neurohormone concentrations of samples col-lected after 30 min of bed rest on the first visit are reportedin Table 1, as are the concentrations for samples collecteddirectly after the subjects arrived and the samples col-lected after 30 min of sitting and after 30 min of standingand walking. The concentrations in Table 1 are alsoexpressed as percentages of the individual neurohormoneconcentrations after 30 min of bed rest. ANOVA analysisshowed that the difference between the four procedures issignificant for all neurohormones, but posttests withBonferroni correction indicated that the differences in thenatriuretic peptides were small and often (with BNP) notsignificant. In contrast to the well-known fact that RENand ALDO vary quite considerably under different blood-sampling conditions, natriuretic peptides appeared to bemuch less variable. Samples collected directly after pa-tients arrived gave somewhat higher values, but valuesobtained during quiet sitting were indistinguishable fromthose obtained during bed rest. For Nt-ANP, the differ-ences were the smallest, which was not surprising in viewof its relatively long half-life. These findings agree withthe results of Wijbenga et al. (6 ), who, in a study on theresponse of natriuretic peptides to exercise, found thehighest percentage of change in ANP, a smaller percent-age of change in BNP, and the smallest percentage ofchange in Nt-ANP. Nt-BNP, which was measured in thatstudy (6 ) but not in our present study, changed more thanNt-ANP but less than BNP. For the catecholamines RENand ALDO, there were considerable differences in thevalues obtained directly after arrival and after 30 min ofbed rest, but the differences between the values obtainedafter 30 min of sitting and after 30 min of bed rest weremuch smaller. Furthermore, Bonferroni posttests pro-duced statistically significant results for ALDO only. Thelack of statistical significance for the difference betweensitting and bed rest values for NOR and adrenalineTable 1. Neurohormone data at first visit for the 23 subjects.ANP,pmol/LBNP,pmol/LNt-ANP,pmol/LNOR,ng/LADR,ang/LALDO,ng/LREN, mgAngI z L21 z h21Basal values (after 30 min of bed rest)Mean 6 SD 52 6 28 6.1 6 7.2 448 6 292 273 6 127 30 6 26 91 6 48 19.0 6 31.5Range 26–122 0.7–27.0 72–1152 114–700 6–116 19–185 2.2–112.6% of basal (mean 6 SD) when sampledDirect sampling 124 6 49b 114 6 23 108 6 15b 186 6 59b 190 6 99b 162 6 55b 126 6 30bAfter 30 min of sitting 99 6 20 101 6 17 104 6 12 127 6 33 122 6 37 128 6 31b 112 6 18After 30 min of standing/walking 114 6 29 116 6 36 110 6 16b 228 6 95b 155 6 54b 159 6 90b 129 6 42bANOVA P value 0.0046 0.0188 0.0066 ,0.0001 ,0.0001 ,0.0001 ,0.0001a ADR, adrenaline; AngI, angiotensin I.b Significantly different from basal.964 Technical Briefscontrasts with previous findings from our laboratory (7 ).In that study, however, only young healthy subjects tookpart, whereas in the present study, subjects were older,and most had diseases associated with an activation of thesympathetic nervous system. We should mention that inyounger subjects, some neurohormones may have agreater response than in the group of older subjects westudied. The effects of medication used by all patientsmay have also played a role.At the second visit (again as a percentage relative to thesamples collected at the first visit after 30 min of bed rest),the pattern was much the same as at the first visit. Thedifference between the four procedures was significantfor all neurohormones, and posttests broadly showedsimilar results as on the first visit. Correlations betweenabsolute values for the same blood-sampling procedure atthe first visit vs those at the second visit were all signifi-cant, except for NOR after 30 min of standing andwalking. A good impression of individual differencescould be obtained by constructing Bland–Altman plots(8 ), which are shown for the natriuretic peptides in thesitting situation in Fig. 1. These indicate that althoughusually there was good agreement between measure-ments on the two different visits, occasionally a largedifference was found. This could be a result of the timingof the medication used (e.g., the effects of angiotensin-converting enzyme inhibitors on REN and ALDO values),but sometimes also for no apparent reason. Here again,the differences in Nt-ANP and BNP appeared to be thesmallest.Which of the various natriuretic peptides is (are) mostinformative with regard to the diagnosis, course, andtreatment of heart failure is still being debated. From theviewpoint of stability in blood samples, the N-terminalpeptides, as well as BNP, appear to be the best (9–13).ANP is less stable, although not as unstable as has beensuggested (14 ). In addition, because of longer half-lives,short-term fluctuations will have less of an effect on themeasured concentrations of the N-terminal peptides thanof the C-terminal peptides. However, clinical studies areneeded to determine which is (are) the most informative.We conclude that the measurement of natriuretic pep-tides in a single blood sample, obtained after 30 min ofquiet sitting, can give reliable and reproducible basalvalues. Measurements of the catecholamines REN andALDO in the same blood sample are only marginallyhigher than values obtained after 30 min of bed rest.Especially for BNP and Nt-ANP, blood sampling directlyafter arrival may be a reasonable alternative when timeand/or facilities are limited.References1. Sagnella GA. Measurement and significance of circulating natriuretic pep-tides in cardiovascular diseases [Review]. Clin Sci 1998;95:519–29.2. Clerico A, Iervasi G, Mariani G. Pathophysiologic relevance of measuring theplasma levels of cardiac natriuretic peptide hormones in humans [Review].Horm Metab Res 1999;31:487–98.3. Clerico A, Del Ry S, Giannessi D. Measurement of cardiac natriuretichormones (atrial natriuretic peptide, brain natriuretic peptide, and relatedpeptides) in clinical practice: the need for a new generation of immunoassaymethods. Clin Chem 2000;46:1529–34.4. van der Hoorn FA, Boomsma F, Man in ’t Veld AJ, Schalekamp MADH.Determination of catecholamines in human plasma by high-performanceliquid chromatography: comparison between a new method with fluores-cence detection and an established method with electrochemical detection.J Chromatogr 1989;487:17–28.5. Derkx FHM, Tan Tjiong L, Wenting GJ, Boomsma F, Man in ’t Veld AJ,Schalekamp MADH. Asynchronous changes in prorenin and renin secretionafter captopril treatment in patients with renal artery stenosis. Hypertension1983;5:244–56.6. Wijbenga JAM, Balk AHMM, Boomsma F, Man in ’t Veld AJ, Hall C. Cardiacpeptides differ in their response to exercise. Eur Heart J 1999;20:1424–8.7. Tulen JHM, Boomsma F, Man in ’t Veld AJ. Cardiovascular control andplasma catecholamines during rest and mental stress: effects of posture.Clin Sci 1999;96:567–76.8. Bland JM, Altman DG. Statistical methods for assessing agreement betweentwo methods of clinical measurement. Lancet 1986;1:307–10.9. Hall C, Aaberge L, Stokke O. In vitro stability of N-terminal proatrialnatriuretic factor in unfrozen samples: an important prerequisite for its useas a biochemical parameter of atrial pressure in clinical routine. Circulation1995;91:911.10. Davidson NC, Coutie WJ, Struthers AD. N-terminal proatrial natriureticpeptide and brain natriuretic peptide are stable for up to 6 h in whole bloodin vitro. Circulation 1995;91:1276–7.11. Cleland JGF, Ward S, Dutka D, Habib F, Impallomeni M, Morton IJ. Stabilityof plasma concentrations of N and C terminal atrial natriuretic peptides atroom temperature. Heart 1996;75:410–3.12. Murdoch DR, Byrne J, Morton JJ, McDonagh TA, Robb SD, Clements S, et al.Brain natriuretic peptide is stable in whole blood and can be measured usinga simple rapid assay: implications for clinical practice. Heart 1997;78:594–7.13. Buckley MG, Marcus NJ, Yacoub MH, Singer DRJ. Prolonged stability of brainnatriuretic peptide: importance for non-invasive assessment of cardiacfunction in clinical practice. Clin Sci 1998;95:235–9.14. Bhaggoe UM, Boomsma F, Admiraal PJJ, Man in ’t Veld AJ, SchalekampMADH. Stability of human plasma atrial natriuretic peptide during storage at280 °C. Clin Chim Acta 1993;223:179–84.Fig. 1. Bland–Altman plots of absolute differences in ANP, BNP, and Nt-ANP between the two visits (blood sampling after 30 min sitting).Clinical Chemistry 47, No. 5, 2001 965

Relationship between natriuretic peptide concentration in plasma and posture during blood sampling

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Relationship between natriuretic peptide concentration in plasma and posture during blood sampling

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