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. 2008 Jul;72(4):356–361.

Cardiac isoenzymes in healthy Holstein calves and calves with experimentally induced endotoxemia

Simon F Peek 1,✉, Fred S Apple 1, Mary Ann Murakami 1, Peter M Crump 1, Susan D Semrad 1
PMCID: PMC2442679  PMID: 18783025

Abstract

This paper describes a controlled study designed to establish normal values for cardiac troponins I and T (cTnI and cTnT) and CK-MB mass in healthy newborn Holstein calves, and to compare values for cTnI, cTnT, CK-MB and total creatine kinase (CK) with age-matched calves experiencing experimentally induced endotoxemia. Nineteen healthy Holstein bull calves, 48 to 72 h of age were used. Baseline cTnI, cTnT, CK-MB and total CK measurements were obtained from control (n = 9) and experimental (n = 10) calves. Controls then received physiological saline and experimental calves received endotoxin (O55:B5 Escherichia coli LPS) intravenously after which cardiac biomarkers and total CK were measured at 3 h, 6 h, 12 h, and 24 h post-initiation of infusion. Measured values were analyzed and compared using analysis of variance (ANOVA) by repeated measure design, with statistical significance set at P < 0.05. The cardiac biomarker cTnT was not detected in any calf at any time point, and CK-MB was only detected in 5 of 95 samples. The cTnI was significantly increased compared to baseline and controls, 3 h post lipopolysaccharide (LPS) infusion. Total CK was significantly increased in LPS administered calves at 18 and 24 h post infusion. The mean, standard deviation, and range for cTnI in healthy controls were 0.023 ng/mL (s = 0.01), and 0.01 to 0.05 ng/mL, respectively. In conclusion, LPS administration was associated with rapid and significant increases in cTnI but CK-MB and cTnT were not detected in the plasma of healthy calves. Total CK values increased significantly following LPS administration. Biochemical evidence of myocardial injury occurs within 3 h following LPS administration to neonatal Holstein calves.

Introduction

Endotoxemia and its pathophysiologic sequelae are well documented consequences of gram-negative infection in both adult and neonatal cattle (1–3). It can arise in cattle in association with organ system infections such as those encountered during enteritis, mastitis, and metritis as well as true gram-negative bacteremia in neonates and adults (4–7). The complex series of pathophysiologic events that are triggered by endotoxemia involve systemic inflammatory response syndromes (SIRS) that can be seen consequent to either whole cell bacterial infection or triggered by the components of the outer cell wall, namely lipopolysaccharide (3,8,9). Endotoxemia in cattle has demonstrable effects on cytokine expression, gastrointestinal function, standard metabolic and hematologic parameters, and cardiac and cardiopulmonary function (1–3,6–8,10). Experimental evidence suggests that some of the adverse metabolic effects, such as those on blood glucose, are dose dependent (8).

Within both skeletal and cardiac muscle the 3-unit troponin complex comprised of troponin I, troponin T, and troponin C is mainly located on actin filaments and its calciummediated interaction with tropomyosin is essential in the regulation of muscle contraction. There is also a small “free” cytosolic pool of these troponins within myocytes that is highly labile and released acutely following cellular injury (11,12). Following cardiac myocyte cell death due to ischemia, for example, there is a rapid release of the free troponins followed by a slower release of structural troponins over the ensuing hours (13). The fact that the human cardiac isoform of troponin I is highly tissue specific and markedly dissimilar to other troponin I isoforms has made it an obvious and attractive diagnostic marker for cardiac myocyte injury. Although troponin T is encoded for by 3 different genes in humans and cTnT has far greater nucleic and amino acid sequence homology with other tissue isoforms than does cTnI, the development of commercially available highly specific 3rd generation monoclonal antibody assays has improved the specificity of diagnostic testing for cardiac injury using this marker also (14). Using currently available assays such as those utilized in this study, elevations in cTnI and cTnT are measurable in blood from patients with acute cardiac syndromes within 6 h of the onset of clinical signs (13). Evidence from animal models suggest that troponin release from cardiac myocytes occurs as quickly as 20 minutes after the onset of ischemia (15), but in the hospital setting current recommendations are that human patients with acute coronary events be monitored repeatedly by serial measurements over several days. Only the half-life in the serum of human cTnI has been established, with a value of approximately 90 minutes (15), indicating that ongoing myocardial release over several hours to days must occur following pathologic insult in order for the observed elevations over the ensuing days to occur in patients with acute coronary syndromes. Currently both cTnI and cTnT are considered the gold standard biomarkers for acute myocardial infarction (MI), elevating within 6 h of the inciting event (12).

There is also direct evidence from the human literature that sepsis, septic shock, and several other noncardiac syndromes can cause cTnI and cTnT elevations, and that during septic shock, troponins are markers of left ventricular dysfunction (16–18). This association between sepsis and cardiac biomarker elevation has been seen in both human neonatal and older patient populations. In patients with sepsis or septic shock cTnI may predict myocardial dysfunction and an adverse outcome (19,20). Consequently, this controlled study measured the cardiac biomarkers cTnI, cTnT, CK-MB, and creatine kinase (CK) in healthy calves as well as those with experimentally induced endotoxemia. Because LPS administration to calves can be associated with life-threatening hypoglycemia (3,8) all LPS recipient calves received dextrose either by constant rate infusion or bolus injection. In order to make direct, statistically appropriate comparisons, 2 of the 3 control groups also received dextrose using the same infusion or bolus methodology. Our hypothesis was that LPS administered calves would have biochemical evidence of myocardial damage that was detectable within 24 h.

Materials and methods

Animals

Nineteen Holstein bull calves between 24 and 48 h of age were acquired from local dairies in south central Wisconsin. Each calf underwent a complete physical examination, including complete blood (cell) count (CBC) and differential examination and fibrinogen quantitation using whole blood obtained by jugular venipuncture. Qualitative evaluation of passive transfer was also done, using a commercially available colorimetric immunoassay (Whole Blood Calf IgG Midland Quick Test Kit; Midland Bioproducts Corporation, Boone, Iowa, USA). This commercial immunoassay has been shown to demonstrate a sensitivity of 99% and a specificity of 89% when compared to the gold standard of specific IgG quantitation, thus giving it superior accuracy to total protein evaluation by refractometer (21).

All calves used in the study had normal physical examination findings, normal CBC and normal differential and fibrinogen levels, and were assessed to have adequacy of passive transfer by virtue of the results of the commercial immunoassay.

Calves were fed commercial milk replacer (Calf-Glo; Vita Plus Corporation, Madison, Wisconsin, USA) at 10% of their bodyweight (BW) divided between 2 meals daily for approximately 36 to 48 h before the onset of the study. All calves were fed 1 hour before study initiation.

The cattle were maintained in individual pens in a research facility accredited by the Association for Assessment of Laboratory Animal Care (AALAC), and all experimental procedures were approved by the University of Wisconsin Institutional Animal Care and Use Committee.

Study design

Calves were divided into control (n = 9) and experimental (n= 10) groups. Separate intravenous catheters (Abbocath-T 14G; Abbott Laboratories, Abbott Park, Illinois, USA) were placed in both jugular veins of each calf under manual restraint. Control calves received normal physiologic saline (0.9% NaCl; Baxter Healthcare Corporation, Deerfield, Illinois, USA) infused at 50 mL/h over a 3-h period, whilst experimental calves received O55:B5 Escherichia coli LPS at 10 μg/kg administered in normal physiologic saline at an infusion rate of 50 mL/h over the same 3-h time period according to a previously described protocol (8). Following the 3-h infusion period calves were divided into the following control and experimental groups:

Controls

  • i) Group 1 (n = 3): were fed milk replacer (4% of BW q6h), beginning 6 h after completion of saline infusion.

  • ii) Group 2 (n = 3): received a constant rate infusion of 10% dextrose solution at 6 mg/kg BW/min beginning immediately following completion of saline infusion.

  • iii) Group 3 (n = 3): received 6 mg/kg BW of 10% dextrose as a bolus infusion over 15 min, every 6 h, beginning immediately following completion of saline infusion.

Experimental animals

  • iv) Group 4 (n = 5): received a constant rate infusion of 10% dextrose solution at 6 mg/kg BW/min beginning immediately following completion of LPS infusion.

  • v) Group 5 (n = 5): received 6 mg/kg BW of 10% dextrose as a bolus infusion over 15 min, every 6 h, beginning immediately following completion of LPS infusion.

From the onset of LPS administration to the end of the 24-h sampling period, calves were monitored hourly for changes in attitude, respiratory rate and effort, and fecal production. Mucus membrane color, capillary refill time, and the presence of a suckle reflex were monitored every 3 h. During the 3-h period of endotoxin infusion, experimental calves demonstrated characteristic clinical signs consistent with endotoxemia; specifically mild tachypnea, mild pyrexia, and depression (increased tendency to lie down, loss of suckle reflex). During the following 21-h period of treatment with intravenous glucose by constant rate infusion or bolus administration, calves were continually observed and monitored, as described, for worsening clinical signs. Several calves demonstrated moderate diarrhea during this time period. No experimental animal required additional treatment during the 24-h of the study, and all calves returned to normal in the 48-h period following the study. No adverse effects were seen in any of the control animals. All experimental and control calves were sold commercially following the conclusion of the study.

Samples for cardiac biomarker and total CK analyses

Serum samples were obtained from all control and experimental animals at T = 0, +3 h, +6 h, +12 h, and +24 h post-initiation of saline or LPS infusion. Analyses were performed for total CK, CK-MB, cTnI, and cTnT.

Cardiac biomarker assays

Serum samples were centrifuged within 2 to 4 h of collection, the serum was then aliquoted and stored at −20°C and later batched for analysis. Cardiac troponin I was measured by the ACCESS Immunoassay (Beckman Instruments, Fullerton, California, USA), a second-generation, 2-site chemiluminescent assay that uses 2 mouse monoclonal antibodies directed against human cTnI. The lower limit of detection for this assay is 0.01 ng/mL. Cardiac troponin T was measured using the Elecsys 2010 Immunoassay (Roche Diagnostics, Indianapolis, Indiana, USA), a 3rd-generation, 2-site electrochemiluminescent assay that uses 2 mouse monoclonal antibodies directed against human cTnT. The lower limit of detection for this assay is 0.009 ng/mL. The CK-MB mass measurements were performed using the Elecsys 2010 assay (Roche Diagnostics), with a lower limit of detection of 0.1 ng/mL. Total CK activity was measured using the Ortho-Clinical Diagnostics Vitro 950 analyzer (Ortho-Clinical Diagnostics, Raritan, New Jersey, USA) with a detection limit of 20 IU/L.

Statistical analyses

Measurements of cTnI, cTnT and CK-MB mass were used to generate summary statistics for each parameter in healthy, neonatal Holstein calves (mean, standard deviation, and range for parameters with Gaussian distribution and median, mode, range, and quartile ranges for those with non-Gaussian distribution). To generate these summary statistics, the sample values obtained from the milk-fed controls at all time points, and the T = 0 samples from the other control and experimental animals were pooled.

For each of the biochemical markers measured (cTnI, cTnT, CK-MB mass, and total CK) further statistical analyses were performed using ANOVA by repeated measure design with significance set at P < 0.05. Analyses were performed comparing time point specific values between experimental groups, as well as to baseline (T = 0) values between controls and experimental groups. Further comparisons were also made between time specific values from each experimental group and controls. Statistical analyses were performed using a commercially available software program (SAS 9.1.3; SAS Institute, Cary, North Carolina, USA).

Results

The CK-MB biomarker was undetectable in 90 of the 95 samples analyzed; of the 5 samples that had detectable levels, all were obtained from 3 experimental calves that had received LPS and that were subsequently administered glucose by bolus injection. No significant differences in CK-MB were observed between controls and experimental animals. Cardiac troponin T was not detected in any calf at any time point. Cardiac troponin I was above the lower limit of detection in all of the 95 samples tested, and in normal healthy calves demonstrated a Gaussian distribution with a mean value of 0.026 ng/mL (s = 0.014; range, 0.01 to 0.07 ng/mL). Mean values for cTnI in experimental and control calves at each time point are described in Figure 1. Mean cTnI values in the LPS recipients that received glucose by infusion or bolus were significantly greater than control values (P < 0.05) at the T = 3 h, T = 6 h, T = 12 h time points. Mean cTnI values were also significantly greater in calves (P < 0.05) that received LPS followed by glucose by bolus at the T = 24 h time point compared to controls. Mean values of cTnI were also significantly greater for LPS recipients that received glucose by infusion or bolus compared to their group specific T = 0 sample at the T = 3 h time point, and in those that received glucose by bolus at the T = 6 h time point.

Figure 1.

Figure 1

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Mean serum cTnI in normal Holstein calves and calves receiving lipopolysaccharide (LPS).

LPSGI — calves received LPS followed by glucose by infusion. LPSGB — calves received LPS followed by glucose by bolus. Control — calves received saline followed by milk replacer. GB controls — calves received saline followed by glucose by bolus. GI controls — calves received saline followed by glucose by infusion. * — mean value was significantly different compared with control value at that time point. a — mean value was significantly different from the T = 0 value for that group of calves.

Total CK values in normal healthy calves were also normally distributed and demonstrated a mean of 44 IU/L, a standard deviation of 21.6, and a range of 7 to 85 IU/L. Mean values for total CK in experimental and control calves at each time point are described in Figure 2. Mean total CK values were significantly greater (P < 0.05) in LPS recipients that received glucose by infusion or bolus at the 24-h time point and at the 12-h time point for those that received glucose by bolus compared with control values. In each case, these mean values were also significantly greater than the group specific T = 0 values.

Figure 2.

Figure 2

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Mean serum creatine kinase in normal Holstein calves and calves receiving lipopolysaccharide (LPS).

LPSGI — calves received LPS followed by glucose by infusion. LPSGB — calves received LPS followed by glucose by bolus. Control — calves received saline followed by milk replacer. GB controls — calves received saline followed by glucose by bolus. GI controls — calves received saline followed by glucose by infusion). * — mean value was significantly different compared with control value at that time point. a — denotes mean value was significantly different from the T = 0 value for that group of calves.

Conclusions

In this study we were able to demonstrate significant increases in cTnI values following experimental induction of endotoxemia in calves compared to controls. This is the first time that biochemical evidence of cardiac injury has been documented in calves with endotoxemia. Previous research has demonstrated several perturbations in cardiopulmonary physiology during experimental endotoxemia in calves to include increases in heart rate, pulmonary artery pressure, left ventricular contractility, chamber stiffness, and mechanical efficiency alongside decreases in left ventricular stroke work, mean systemic blood pressure, and cardiac output (10,22,23). However, there are no reports in the veterinary literature documenting biochemical damage, although there is evidence from human critical care medicine that cTnI elevations do occur both following experimental administration of endotoxin to human subjects (17) and in spontaneous non-cardiac conditions such as septic shock, stroke, renal failure, and pulmonary thromoembolism (16,19,24). Our conclusion that the measured increases in cTnI represent cardiac damage in experimental animals is predicated on an assumption of specificity for cTnI and myocardial injury using the reagents and assays in question. There is strong evidence to support this conclusion, based upon the comparative study by O’Brien et al (25) that demonstrated cTnI as being highly specific to myocardium in calves using the same immunoassay as was employed herein. The mouse immunoassay used to measure cTnT has also been demonstrated to be cross-reactive and specific to bovine myocardium compared to skeletal muscle (26) but there were no positive sample measurements for this biomarker in our study. This suggests that cTnT is not a good candidate biochemical marker for myocardial injury in cattle, at least not using the currently available Roche immunoassay based on mouse monoclonal antibodies. The authors were only able to find 1 article describing CK-MB in cattle; a single case report detailing a cow with myocardial infarction and CK-MB elevation (27). In the present study, we were only able to detect CK-MB in 5 samples from 3 experimental calves, each of which were receiving glucose by bolus injection following LPS administration. Each of these 3 calves also had cTnI elevations well above the mean values for the study at coincident or earlier time points. This suggests that CK-MB is a less sensitive biomarker for myocardial injury than cTnI, although it is not possible to entirely rule out skeletal muscle as a false positive source of CK-MB elevation in these 3 calves since there was no information on the specificity for CK-MB in cattle with the assay used in this study. The poorer specificity of CK-MB for myocardial infarction in humans compared to the troponins has meant that this parameter is not analyzed as frequently in patients with presumed acute coronary syndromes. When interpreting the lack of cTnT and CK-MB elevations in LPS administered calves herein, it is also relevant to consider the kinetics of release of these proteins into the circulation. There are no data that detail the time frame over which cTnI, cTnT, or CK-MB are released into the peripheral circulation in cattle and so the selection of multiple time points in the 24 h following LPS administration was somewhat empiric and based upon human data. For cTnI and cTnT in humans, evidence exists that release into the circulation occurs within 6 h of an acute cardiac insult (13) and so the sample time points were selected with this in mind, mirroring what is seen in humans. Because ongoing troponin release may occur in the days following an acute coronary syndrome in humans, it is possible that the 24-h sample window post LPS infusion missed later cTnT elevations in some calves, but this seems unlikely. With reference to CK-MB, again there is no literature on the kinetics of release in cattle, but by analogy with the enzyme in humans (29) and dogs (30) where measurable elevations occur and peak within a few hours of cardiac insult, we would expect to have been able to measure values in our 24-h sample window. An explanation as why neither cTnT nor CK-MB were reliably elevated in LPS recipient calves could be the different release kinetics in cattle compared to other species, lack of assay sensitivities, or merely because the severity of cardiac insult was not great enough.

It is possible that the study design, with multiple small groups of both experimental and control calves, negatively impacted the statistical power that could be achieved in attempting to define differences in troponin and CK-MB values between LPS recipient calves and controls. Prior experience of one of the investigators (Semrad, unpublished data 2003) using LPS challenge in neonatal calves had demonstrated that glucose homeostasis is more consistent with constant rate infusion rather than by bolus; an attempt was made to validate that herein. The study was therefore designed with 3 control and 2 experimental groups, and 2 different ways of dextrose administration, partly to minimize use of live animals in research. Statistical analyses did not demonstrate any significant differences in any of the parameters measured (CK-MB, total CK, cTnI, and cTnT) between LPS recipient calves that received dextrose either by infusion or by bolus suggesting that there is no cardioprotective effect of dextrose administration following LPS infusion using one method compared with the other.

The LPS administered calves in this study demonstrated some of the typical clinical signs of endotoxemia including tachypnea, depression, and diarrhea. Extensive cardiac imaging or function tests to establish whether or not there was ultrasonographic evidence of myocardial dysfunction in the LPS administered calves compared to controls were not performed. Regrettably, detailed histopathologic examination of myocardium was not performed on any of the experimental animals as this was a nonterminal study. It is possible that LPS mediated myocardial damage via a number of potential mechanisms to include direct cytotoxic injury, ischemia related to hypoperfusion, and transient hypoglycemia during the period of infusion. More detailed light and electron microscopic evaluation of cardiac muscle as well as potential non-cardiac sources of these proteins (skeletal muscle for example) from those calves with troponin and CK-MB elevations may have allowed us to more specifically address the issues of origin and pathophysiology of biomarker release during endotoxemia and SIRS. It was interesting to note that the only calves in the entire study with measurable CK-MB elevations were those that received LPS followed by glucose by bolus, and these were also individuals with high cTnI values at the same time point. Although the highest mean CK values at all time points and the highest mean cTnI values at 3 of the 4 sampling periods were observed in LPS administered calves that received glucose by bolus at no point were there statistically significant differences in these 2 variables between experimental calves that received glucose by infusion versus those that received glucose by bolus.

The only previous literature examining cardiac troponins in naturally occurring or experimentally induced disease in cattle is a single case report describing a calf with foot-and-mouth disease, histologically confirmed myocarditis, and detectable cTnI and cTnT in plasma (28). The methodology in that paper involved the purely qualitative “rapid patient side” commercial kits available for human use, which was very different from that used herein. There are a number of spontaneous diseases in cattle in which early biochemical detection of myocardial injury would be helpful in choosing appropriate management or treatment, or both. Cattle with nutritional myodegeneration, viral myocarditis, calves with sepsis, and, based upon this study, cattle with systemic inflammatory response syndromes associated with gram-negative infections such as enteritis, mastitis, and metritis may all be at risk for myocardial injury. However, further studies that more precisely define the link between biochemical changes, functional cardiac deterioration and prognosis are needed.

Acknowledgments

The authors thank the University of Wisconsin’s Food Animal Research Program at the School of Veterinary Medicine for financial support of this project. We are also grateful to Steve Mell for obtaining and transporting the calves used in this study.

Footnotes

This study was funded through a grant from the University of Wisconsin Food Animal Research Grant Program. Printed in abstract form for the International Veterinary Emergency and Critical Care Meeting in Atlanta, USA, September 2005.

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