In 28 patients with acute myocardial infarction, the release pattern of 2, 3-butanediol (BD), a product of intermediary metabolism, and creatine kinase activity (CK) in blood were compared. Whereas CKat entry was low in all patients, the BD level was elevated in 18 (64%). However, BD returned to normal levels during the next 24 h whereas CK increased. The BD level at entry did not allow differentiation between patients with transmural or non-transmural infarction; it was independent of clinical findings and biochemical parameters. We suggest that, in patients with acute myocardial infarction, elevated levels of BD originates from myo-cardial metabolism. Whether it reflects ongoing ischaemia or reperfusion of the infarcted area remains unresolve

HEER, K. R.

STALDER, H.

THOELEN, H.

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European Heart Journal (1990) 11, 788-790Early appearance of 2,3-butanediol in acute myocardialinfarction. A new marker for ischaemia?K. R. HEER, H. STALDER AND H. THOELENDepartement Forschung Kantonsspital Basel, andMedizinische Abteilung Kantonsspital Liestal, SwitzerlandKEY WORDS: Acute myocardial infarction, 2,3-butanediol, ischaemia.In 28 patients with acute myocardial infarction, the release pattern of 2,3-butanediol (BD), a product ofintermediary metabolism, and creatine kinase activity (CK) in blood were compared. Whereas CKat entrywas low in all patients, the BD level was elevated in 18 (64%). However, BD returned to normal levels duringthe next 24 h whereas CK increased. The BD level at entry did not allow differentiation between patients withtransmural or non-transmural infarction; it was independent of clinical findings and biochemical parameters.We suggest that, in patients with acute myocardial infarction, elevated levels of BD originates from myo-cardial metabolism. Whether it reflects ongoing ischaemia or reperfusion of the infarcted area remainsunresolved.IntroductionIn the early phase of myocardial infarction, nobiochemical parameter for myocardial ischaemia isknown in the peripheral venous blood. Elevation ofplasma creatine kinase occurs late and indicatesmyocardial injury or cell necrosis. A biochemicalparameter for ischaemia however could be import-ant for stratifying patients with acute chest pain.2,3-butanediol (BD) is a product of intermediarymetabolism; its precursors are pyruvate, acetalde-hyde and acetoin'1'2'. In his studies of the enzymaticsynthesis and breakdown of acetoin in the animalorganism, Jarnefelt has shown that, under anaero-bic conditions, the formation of BD is accelerated'31.In a preliminary study we found elevated levelsof BD in some patients with acute myocardialinfarction.We report a prospective study of 28 patients withacute myocardial infarction. In addition to conven-tional clinical, electrocardiographic and enzymatictechniques we performed frequent serial determi-nations of BD to assess its release pattern.Patients and methodsOf 121 consecutive patients with chest pain whowere admitted to the coronary care unit, 21 men and7 women (age 42 to 84 years) were included in theprospective study. All 28 patients had typical chestSubmitted for publication on I November 1988, and in revised form24 November 1989.Address for corrapondenct K. R_ Heei, ICasernenstrasse 22A. 4410Liestal, Switzerland.pain of at least 30 min duration, which had occurredwithin the preceding 6 h. Serial electrocardiogramsshowed in all cases either Q wave evolution ortypical S-T wave changes. Increase of CK activityduring the first day was noted in 22 patients. As areference group, we determined BD in 23 patientswith stable angina pectoris (aged 29-78 years).For the analysis of 2,3-butanediol, 10 ml samplesof venous blood were taken at 2,4,6,9,12 and 24 hafter the onset of pain. The blood was deproteinizedimmediately with sulphuric and tungstic acid. Thesupernatant was frozen at — 20 °C and stored. Thesamples were analysed according to the methoddescribed by Happold and Spencer'4' andWesterfeld'51.2,3-butanediol in the supernatant wasoxidized to diacetyl with bromide and ferrichloride;diacetyl was reacted with 2,4-dinitrophenylhydra-zine. The precipitated hydrazone was filtered anddetermined colorimetrically. The relative coef-ficient of variation was less than 5%; normal levelsare below 0029 mmol I"1. The results were obtain-able within 8 h. CK activity was measured with acommercially available diagnostic kit (Merck);normal values are below 80 U1" ' .Results are expressed as the mean±SD (SEMwhere noted). Unpaired Student's r-test was usedfor statistical analysis.ResultsIn a group of 28 patients with acute myocardialinfarction, BD showed a release pattern contrast-ing to the rise of CK during the first 24 h (Fig. 1).0195-668X/90/090788 + 03 J03.00/0 © 1990 The European Society of Cardiotogy2,3-butanediol as a marker of ischaemia 789At entry, 18 of 28 patients had elevated levelsof BD, 0087 ±0036 mmoir 1 (range 0055-0-188 mmol I"1), which decreased to normallevels within 24h, 0025±0-015 mmoir 1 . In 10other patients, BD was found to be normal atentry, 0012±0006 mmol I"1 (range 0006-0026 mmol 1"'); in eight it remained normal duringthe 24 h, whereas in two minor changes were noted.No significant difference in history (unstable anginapectoris and old myocardial infarction), clinicalpresentation at entry (Killip), duration of chest painor need for antiarrhythmic therapy was foundbetween patients with high or low levels of BD. Therelease of BD was independent of time of admissionand history of alcohol consumption. In 23 patientswith stable angina pectoris the mean value ofBD was 0015±0005mmol 1"' (range 0-008-0-029 mmol I"1).Twenty-one patients showed a typical rise in CKduring the first 24 h; CK was higher in transmuralthan in non-transmural infarction. No or little risein CK was found in four patients with low BD andin three patients with high BD at entry; they allhad non-transmural infarction. There was no directrelationship between BD level and CK activity;however patients with high BD at entry showed anon-significantly higher level of CK 9 h after theonset of chest pain. In addition, patients withtransmural infarction had a significantly higher BDlevel at 12 h than patients with non-transmuralinfarction (P< 0-02).Two patients died; both were in cardiogenicshock on admission and both had transmuralinfarction. Their BD levels were 0-017 mmol I"1 and0-049 mmoir1 .DiscussionBD at entry in 28 patients with acute myocardialinfarction was found to be significantly differentfrom BD in a group of 23 patients with stableangina pectoris (P < 0-001). However, a differencein release pattern was noted within the group ofacute myocardial infarction patients. In 18 of 28patients (64%), BD was elevated at entry andreturned to normal within 24 h; in 10 patients (36%)BD remained normal during the study period. Thisdifferent pattern was related neither to the localiz-ation or extent of the infarction nor to clinicalparameters. However at 12 h after the onset of pain,BD was significantly higher in patients with trans-mural infarction (Fig. 1). We suggest that BD is aproduct of ischaemic myocardial metabolism whichoio -O-O5 -1000 -500 -24Hours afttr onset of painFigure I 2,3-butanediol (a) and creatine kinase (b) duringthe first 24 h in 28 patients with acute myocardial infarction(mean±SEM). Open area: transmural infarction; dashedarea: non-transmural infarction.is released early into the peripheral circulation,unlike CK, which is found in blood only after somehours. This is supported by the study of Jarnefeltwho showed that BD is produced in heart muscleand that production is increased under anaerobicconditions'31. We suppose that BD crosses the cellu-lar membrane early in the course of ischaemia, asdoes lactate which can be found in the coronarysinus but not in the peripheral blood'61. Both metab-olites have a low molecular weight. However, it stillremains unresolved whether elevated BD at entryindicates ongoing ischaemia or washout of ischae-mic metabolites by natural reperfusion of theinfarcted area. As evolution of a myocardial infarc-tion is considered to be a dynamic process171, the790 K. R. Heer et al.explanation is even more difficult. The finding thatin patients with transmural infarction BD remainselevated during the first 12 h in comparison tonon-transmural infarction could however be due todynamic alteration of myocardial metabolism andperfusion. In patients with non-transmural infarc-tion this dynamic process would be of shorterduration with earlier reperfusion; however, one cannot exclude the possibility that in these patients theischaemic area at the onset of pain is large enough toproduce substantial quantity of BD. Indeed in 11of 19 patients with non-transmural infarction, BDwas high at entry, 0-083±0-021 mmol I"1 (range0056-0-114 mmoir1) .Different patterns of BD could also be due todifferent metabolism and excretion of the metab-olite itself. However this seems to be less likely,although little is known about metabolism and ex-cretion. Soling et al. concluded from their rat studythat approximately 80% of infused BD wasabsorbed by the peripheral tissue within 2—4 b18'.From their cat studies, Dawson and Hullin came tothe conclusion that BD was rapidly metabolized asa first step (up to 90% within the first hours); thesecond step would be slow1'1. According to obser-vations by Westerfeld and Berg, urinary excretion isminor19'.Elevated levels of BD are also found in patientswith hepatic or uraemic coma'101; rising bloodglucose in diabetics is accompanied by a rising levelof BD1"1. However no patient of our study had renalor hepatic insufficiency or a metabolic disorder.Elevated alcohol intake could be excluded from thepatients' history. They also had no pulmonaryembolism or perimyocarditis.The findings of our study suggest that elevatedBD in blood of patients with acute myocardialinfarction originates from ischaemic myocardialmetabolism. Whether it indicates ongoing ischae-mia or reperfusion still remains unresolved. Furtherstudies are needed to support our results and toclarify their relevance for managing patients withacute myocardial infarction. New and rapid labora-tory methods are needed.We are indebted to Miss Astrid Gysin for technical assist-ance and to the nursing staff of the intensive care unit forobtaining blood samples.References[1] Dawson J, Hullin RP. Metabolism of acetoin. Biochem1954; 57: 177-85.[2] Schreiber G, Kohlhaw G, Goedde HW, Holzer H. DieBiosynthese von Acetoin in Schweineherzrauskel. Bio-chem Zeitschrift 1963; 339:83-93.[3] Jarnefelt J. Studies on the enzymatic synthesis andbreakdown of acetoin in the animal organism. Ann AcadSci Fenn 1955; V: 1-78.[4] Happold FC, Spencer CP. The bacterial formation ofacetylmethylcarbinol and 2,3-butylene glycol. BiochimBiophys Acta (AMST) 1952; 8: 18-29.[5] Westerfeld WW. Colorimetric determination of bloodacetoin. JBiolChem 1945; 161:495-502.[6] Opie LH, Owen P, Thomas M, Samson R. Coronarysinus lactate measurements in assessment of myocardialischemia. Am J Cardiol 1973; 32: 295-305.[7] Davies MJ, Thomas AC. Plaque fissuring — the cause ofacute myocardial infarction, sudden ischemic death, andcrescendo angina. Br Heart J 1985; 53: 363-73.[8] Soling HD, Kohlhaw G, Schnermann J, Holzer H,Creutzfeldt W. Zur Bedeutung des Acetoins fur diePathogenese des Coma hepaticum. Dtsch Med Wschr1964; 10:457-64.[9] Westerfeld WW, Berg RL. Observations on the metab-olism of acetoin. J Biol Chem 1943; 148: 523-8.[10] Thoelen H, Bigler F, Stauffacher W, Staub H. ZurPathogenese des Uramiesyndromes. Brenztraubensaure,Acetoin und 2,3-Butylenglycol in Blut von Patienten mitNieren- und Leberkrankheiten. Experientia (Basel)1962; 18:454-5.[11] Stdcklin MR. Das Verhalten von Brenztraubensaure,Milchsaure, Acetaldehyd, Acetoin, 2,3-Butylenglycolund ph-Wert im Blut bei Diabetes mellitus. Dissertation.University of Basel, 1975.

Early appearance of 2, 3-butanediol in acute myocardial infarction. A new marker for ischaemia?

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