The beta-adrenergic agonist zilpaterol hydrochloride may predispose feedlot cattle to cardiac remodeling and dysfunction

Joseph M. Neary; Franklyn B. Garry; Daniel H. Gould; Timothy N. Holt; R. Dale Brown

doi:10.12688/f1000research.14313.1

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Research Article

The beta-adrenergic agonist zilpaterol hydrochloride may predispose feedlot cattle to cardiac remodeling and dysfunction

[version 1; peer review: 2 approved with reservations]

Joseph M. Neary ¹, Franklyn B. Garry², Daniel H. Gould³, Timothy N. Holt², R. Dale Brown⁴

Joseph M. Neary ¹, Franklyn B. Garry², [...] Daniel H. Gould³, Timothy N. Holt², R. Dale Brown⁴

PUBLISHED 26 Mar 2018

Author details Author details

¹ Department of Animal and Food Sciences, College of Agriculture and Natural Resources, Texas Tech University, Lubbock, TX, USA
² Integrated Livestock Management, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
³ Veterinary Diagnostic Laboratory, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
⁴ Department of Pediatrics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

Joseph M. Neary
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Franklyn B. Garry
Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing

Daniel H. Gould
Roles: Data Curation, Investigation, Methodology, Project Administration, Writing – Review & Editing

Timothy N. Holt
Roles: Investigation, Methodology, Writing – Review & Editing

R. Dale Brown
Roles: Data Curation, Investigation, Project Administration, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background: The aim of this study was to address producer concerns that the β₂-adrenergic agonist zilpaterol hydrochloride, a bovine growth promotant, predisposes cattle to cardiac disease and death. Our objectives were to evaluate the effect of zilpaterol on cardiac function, morphology, and risk of myocardial injury.
Methods: A prospective, case-control study was conducted on one feedlot in northern Colorado using convenience sampling of Angus-based steers (n = 80). Pulmonary arterial pressures (mean, systolic, and diastolic) were measured. Plasma cardiac troponin I was measured in a sub-sample of steers that were followed to slaughter (n = 31). The carcass, left ventricle plus inter-ventricular septum, and right ventricle were weighed.
Results: Relative to controls, steers fed zilpaterol hydrochloride had an adjusted left ventricle and septum that was 185 g heavier (95 % CI: 19, 350 g; P = 0.03), a diastolic pulmonary arterial pressure that was 10 mm Hg greater (95 % CI: 3, 17 mm Hg; P = 0.004), and a greater concentration of cardiac troponin I (P = 0.01), a biomarker of myocardial injury. Furthermore, left ventricular mass tended to be positively and deleteriously associated with diastolic pulmonary arterial pressure in steers fed zilpaterol (P = 0.08) but not controls (P = 0.28).
Conclusions: Our findings suggest that zilpaterol hydrochloride induced sufficient left ventricular hypertrophy to cause impaired left ventricular relaxation or diastolic dysfunction and myocardial injury. In conclusion, these results support concerns that, in the feedlot studied, zilpaterol hydrochloride predisposes cattle to cardiac disease.

Keywords

feedlot, heart, morbidity, mortality, health

Corresponding author: Joseph M. Neary

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2018 Neary JM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Neary JM, Garry FB, Gould DH et al. The beta-adrenergic agonist zilpaterol hydrochloride may predispose feedlot cattle to cardiac remodeling and dysfunction [version 1; peer review: 2 approved with reservations]. F1000Research 2018, 7:399 (https://doi.org/10.12688/f1000research.14313.1) First published: 26 Mar 2018, 7:399 (https://doi.org/10.12688/f1000research.14313.1) Latest published: 26 Mar 2018, 7:399 (https://doi.org/10.12688/f1000research.14313.1)

Introduction

In the United States, two β-adrenergic agonists (βAA) are approved for the purpose of growth promotion in cattle fed in confinement for slaughter: ractopamine hydrochloride¹, a predominantly β₁AA, and zilpaterol hydrochloride², a predominantly β₂AA. In 2011, approximately 57% of cattle in U.S. feedlots were fed a βAA³. Beta-adrenergic agonists are synthetic, structural, and functional analogs of the endogenously produced compound epinephrine (adrenaline). They have the favorable effect of inducing skeletal muscle hypertrophy while decreasing adiposity⁴.

Chronic β-adrenoreceptor stimulation, however, may also cause left ventricular hypertrophy⁵, a strong, independent risk factor for death in humans^6–8. Moreover, a large observational study concluded that 40 to 50% of deaths among feedlot cattle treated with the β₂ adrenergic receptor-selective agonist zilpaterol hydrochloride (Zilmax®, Merck Animal Health, Summit, NJ, USA) were attributable to the drug⁹. The etiology of this increased mortality risk has not been investigated, but anecdotal reports suggest that cattle fed β₂AA are at increased risk of heart failure. This is biologically plausible; mortality associated with chronic use of β₂AA use in humans has been primarily attributed to myocardial disease^10,11.

The aim of this study was to address the concerns that zilpaterol hydrochloride may predispose cattle to heart failure. An in-situ, prospective, case-control study was performed at one feedlot in northern Colorado, U.S.A., to evaluate the effect of zilpaterol hydrochloride on bovine cardiopulmonary physiology, cardiac morphology, and the risk of myocardial injury.

Methods

Ethical considerations

The Colorado State University Animal Care and Use Committee approved of this project (Protocol 13-4451A). Permission to conduct the study at the feedlot and abattoir was granted by the owners prior to the start of sampling. All efforts were taken to ameliorate animal suffering by minimizing the time that steers were restrained for the purposes of this study.

Study site and sampling

Black-hided, Angus-based steers that were within 30 days of slaughter were studied in one feedlot located 1,440 m above sea level in northern Colorado (Table 1). The sample size was limited to 80 due to voluntary market withdrawal of the drug during the course of the study. Cattle were procured from the western U.S. through the auction market system and directly from producers. On arrival at the feedlot the cattle weighed approximately 300 kg. They were vaccinated against bacterial and viral pathogens, injected with an anthelmintic, implanted with a hormone growth promotant, and given an ear tag with a unique identification number. The cattle were harvested approximately 180 days after arrival and were managed per standardized protocols developed by specialists in the areas of feedlot animal health, nutrition, and husbandry. Steers were fed zilpaterol hydrochloride per the label directions: 7.6 g/ton zilpaterol (8.3 ppm on a 100% dry matter basis), to provide 60 to 90 mg zilpaterol hydrochloride per head per day. Steers were fed zilpaterol for 21 days followed by a 7-day withdrawal period, rather than the minimum 3-day period required. Feed and water were always available.

Table 1. The number of cattle tested according to the date of testing in the year 2013.

Date	Control steers	Zilpaterol steers	Total
August 1^st	10	10	20
August 15^th	11	14	25
August 29^th	2	13	15
October 21^st	20	0	20
Total	43	37	80

Steers were chosen from each of 9 and 11 different pens, respectively. Control steers (CS) were selected that had the same, or a similar, slaughter date to zilpaterol treated steers (ZS). Steers were chosen from within each pen in such a way as to minimize animal disturbance. Steers were moved up to the chute individually, or in pairs, so that they spent minimal time within the curved alley. Steers were restrained in a chute for sampling and measurements. The ZS were studied at days 7 (n = 10), 8 (n = 6), 15 (n = 4), and 21 (n = 17) of β₂AA exposure. In total, 35 apparently healthy CS and 28 apparently healthy ZS were sampled. Sixteen of the 80 steers studied, 8 ZS and 8 CS, were treated for respiratory disease at various times while at the feedlot. These animals were not included in the statistical analyses.

The sampling dates (Table 1) were determined by the schedule availability of investigators and feedlot personnel. Sampling was conducted between 8:00 am and 11:00am. In the original study design, approximately equal numbers of ZS and CS were to be sampled each day. This did not occur, however, for two reasons: first, zilpaterol hydrochloride was voluntarily withdrawn from the market on August 16^th, 2013; and second, on August 29^th sampling was called off by the feedlot manager after 2 ZS became highly stressed in the alley and refused to exit. Their rectal temperatures reached 42.2°C (108 °F) (Quicktemp Digital Thermometer, Agripro Enterprises, Iowa Falls, Iowa, USA). The steers were cooled with alcohol poured over the skin and, after approximately 1 hour, walked forwards out of the chute; consequently, only 11 healthy ZS, and 2 ZS and 2 CS that had been treated for respiratory disease, were studied on that day. Following the withdrawal of the drug from the market, only CS were available for further study.

Pulmonary arterial pressure (PAP) measurement

A full description of the equipment, materials, and facilities required for PAP testing is provided elsewhere¹². In brief, an 8.9 cm (3.5 inch) 12-gauge needle was inserted into the jugular vein through which flexible, saline-filled catheter/polyethylene tubing was threaded. The catheter tip was then fed through the right atrium and ventricle and into the pulmonary artery. A pressure transducer connected the catheter to an oscilloscope (BM5Vet, Bionet America Inc., Tustin, CA, USA). The position of the catheter was determined from the pressure waveform on the oscilloscope. The jugular vein, right atrium, right ventricle, and pulmonary artery have distinct pressure waveforms¹². Mean, systolic, and diastolic pressures were recorded after the pulmonary pressure waveforms had stabilized. Diastolic PAP is hemodynamically influenced by left ventricular chamber pressures shortly prior to contraction, and therefore provides an indirect measure of end-diastolic left ventricular filling pressure¹³. Pulmonary arteriolar wedge pressure is a more direct measure of left ventricular end-diastolic pressure. Wedge pressures are, however, more difficult and time-consuming to obtain in cattle because the fluid-filled catheters used are not balloon-tipped; consequently, to minimize the time that cattle spent in the chute, arteriolar wedge pressures were not collected.

Blood analysis

Cardiac troponin I analyses were performed on a single day using plasma samples that had been obtained from all steers that were followed to slaughter. The plasma had been stored at -80° C and thawed at room temperature prior to analysis (cTnI, i-STAT 1, Abaxis, Union City, CA).

Hot carcass weight (HCW) and ventricular weights

In the original study design, all cattle at the feedlot that died within the late feeding period were to be evaluated postmortem throughout the duration of the study. Due to an insufficient number of feedlot personnel, however, postmortem data were not collected. Cardiac dimension data were, therefore, collected at slaughter from the remaining 2 cohorts of steers: the 11 ZS studied on August 29^th, 2013, and slaughtered on September 5^th; and the 20 CS studied on October 21^st and slaughtered on October 29^th, 2013. Only steers that were healthy at the time of sampling and had not been treated for disease while at the feedlot were followed to slaughter.

The steers were slaughtered at a nearby USDA-approved facility. The individual animal identification number of every animal in the study remained with the carcass and heart throughout the slaughter process. This allowed the hot carcass weight (HCW, mass of the unchilled carcass after removal of the head, hide, and viscera) to be paired with cardiac mass. After inspection by a USDA veterinarian, the heart was removed from the processing line, placed in a plastic bag, and stored in ice.

The atria were dissected from the ventricles at the level of the atrioventricular valves and the ventricles subsequently divided into a left ventricle plus inter-ventricular septum (LVS) and right ventricular free wall (RV). The ventricles were weighed using a scale with precision to 0.045 kg (0.1 lb). All cardiac tissue was dissected and weighed within 3-hours of slaughter.

Statistical analyses

Data were analyzed using statistical software (STATA version 12.1, Stata Corporation, College Station, Texas, USA). Statistics are provided as an adjusted average (mean or median) ± 95% confidence interval of the average. The animal served as the experimental unit. Only steers that were apparently healthy at the time of testing and had not been treated for any disease while at the feedlot were included in statistical analyses. Steers that had been treated, or needed treatment, for disease were not included in any statistical analyses due to the small sample size.

Between-group statistical differences in PAP (3 variables) were assessed using quantile regression for nonparametric data while controlling for pen-level clustering (‘qreg2’ command)¹⁴. In subsequent analyses, pen-level clustering was not a concern because ZS and CS that were followed to slaughter belonged to the same 2-pens. Differences in right and left ventricular masses were assessed using linear regression analyses. A Wilcoxon rank-sum test (Mann-Whitney U test) was performed for evaluation of cardiac troponin I due to the non-parametric distribution of residual error about the mean (‘ranksum’ command). Finally, the effect of left ventricular mass per unit of HCW on diastolic PAP was evaluated, stratified by the feeding of zilpaterol. Left ventricular mass per unit of HCW was chosen as the dependent variable rather than LVS because of the potential collinearity between LVS and HCW. A linear regression analysis was performed for ZS and, due to lack of normality of the standardized residuals, quantile regression was performed for CS (‘qreg’ command). Evaluations of model fit included graphical and statistical assessments of residual error normality (Shapiro-Wilk test), heteroskedasticity (Breusch-Pagan/Cook-Weisberg test), and linearity.

Results

The results of this study indicate that, in the feedlot studied, steers fed the βAA zilpaterol hydrochloride had greater left ventricular hypertrophy and plasma cardiac troponin I, a biomarker of myocardial injury, than controls. The mass of the left ventricle tended to be positively associated with diastolic PAP in ZS, but there was no association between left ventricular mass and diastolic PAP in CS.

Pulmonary arterial pressures

Diastolic PAP was 10 mm Hg greater in ZS than CS (95% CI: 3, 17 mm Hg; P = 0.004). Mean and systolic PAP were not statistically different (P > 0.20). Mean PAP was 47 mm Hg (95% CI: 44, 50 mm Hg) in both ZS and CS. Systolic PAP was 80 mm Hg (95% CI: 76, 84 mm Hg) in CS and 82 mm Hg (95% CI: 73, 90 mm Hg) in ZS.

Cattle treated for respiratory disease had greater pressures than healthy cattle. Mean PAP was 57 (95% CI: 36, 78 mm Hg) in CS and 61 (95% CI: 33, 89 mm Hg) in ZS. Systolic PAP was 95 mm Hg (95% CI: 60, 130 mm Hg) in CS and 93 mm Hg (95% CI: 52, 134 mm Hg) in ZS. Diastolic PAP was 20 mm Hg (95% CI: 4, 36 mm Hg) in CS and 37 (95% CI: 16, 58 mm Hg) in ZS.

Cardiac hypertrophy

Steers fed zilpaterol hydrochloride had hypertrophy of the LVS. Steers fed zilpaterol had an adjusted LVS mass that was 185 g (95% CI: 19, 350 g) heavier than CS (P = 0.03). Right ventricular mass did not differ between ZS and CS (P = 0.33). The HCW of ZS was 403 kg (95% CI: 376, 429 kg) and 418 kg (95% CI: 400, 437 kg) in CS (P = 0.29). The adjusted mean mass of the RV was 588 g (95% CI: 526, 650 g) in CS and 535 g (95% CI: 450, 619 g) in ZS. The adjusted mean mass of the LVS was 1.512 kg (95% CI: 1.419, 1.605 kg) in CS and 1.697 kg (95% CI: 1.570, 1.824 kg) in ZS.

The mass of the LVS per unit of HCW tended to be associated with diastolic PAP in ZS (P = 0.08) but not CS (P = 0.28) (Figure 1A). In ZS, a 0.1 kg increase in LVS per 100 kg of HCW was associated with a 9 mm Hg (95% CI: -1, 19 mm Hg) increase in diastolic PAP.

Figure 1. The relationship between A) diastolic pulmonary arterial pressure (PAP) and B) plasma cardiac troponin I with mass of the left ventricle plus inter-ventricular septum (LVS) per 100 kg of hot carcass weight (HCW).

Left ventricular hypertrophy in steers fed zilpaterol hydrochloride tended to be positively associated with diastolic PAP. Cardiac troponin I concentrations were significantly greater in steers fed zilpaterol hydrochloride. The two steers with the greatest left ventricular hypertrophy had the greatest diastolic pulmonary arterial pressures (A) and the greatest cardiac troponin I concentrations (B).

Cardiac troponin I (cTnI)

Plasma cardiac troponin I (cTnI) concentrations were significantly greater in ZS than CS (P = 0.01). The greatest concentrations were observed in the two steers with the most hypertrophied left ventricles (Figure 1B). In CS, the concentrations of cTnI ranged from 0.00 to 0.02 ng/mL; 5% (1 of 20 steers) had a cTnI concentration of 0.02 ng/mL. In ZS, the concentrations of cTnI ranged from 0.00 to 0.04 ng/mL; 36% (4 of 11 steers) had a cTnI concentrations of 0.02 ng/mL or greater. The complete results are as follows: among the 20 CS sampled, 14 (70%) had a cTnI of 0.00 ng/mL, 5 (25%) had a cTnI of 0.01 ng/mL, and 1 (5%) had a cTnI of 0.02 ng/mL; among the 11 ZS sampled, 3 (27%) had a cTnI of 0.00 ng/mL, 4 (36%) had a cTnI of 0.01 ng/mL, 2 (18%) had a cTnI of 0.02 ng/mL, 1 (9%) had a cTnI of 0.03 ng/mL, and 1 (9%) had a cTnI of 0.04 ng/mL.

Discussion

The findings of this study indicate that, in the feedlot studied, the β₂AA zilpaterol hydrochloride is associated with left ventricular hypertrophy and myocardial injury. Furthermore, the tendency in our study for left ventricular mass to be positively and deleteriously associated with diastolic PAP in steers fed zilpaterol hydrochloride suggests that βAA-induced left ventricular hypertrophy likely caused diastolic dysfunction.

Left ventricular hypertrophy is a product of chronic β-adrenoreceptor activation and is a major risk factor for cardiovascular morbidity and mortality in humans and animals^5,15. Two major sequelae of ventricular hypertrophy pertinent to our study are diastolic dysfunction¹⁶ and myocardial ischemia¹⁷. Diastolic dysfunction is defined as failure of the myofibrils to return to their resting length and ventricular filling is slow or incomplete unless atrial pressure increases¹⁶. A hallmark of diastolic dysfunction is an increase in left ventricular end-diastolic pressure¹⁶. End-diastolic pressure is positively correlated with diastolic PAP, even when pulmonary vascular resistance or heart rate is elevated^13,18; consequently, the positive association between left ventricular mass and diastolic pulmonary arterial pressure in steers fed zilpaterol, but not controls, suggests that the myocardial hypertrophic effects of zilpaterol induced diastolic dysfunction. This is not unreasonable: the myocardial hypertrophic action of βAA, such as isoprenaline, are used for the study of diastolic dysfunction in animal models of heart failure^19–21.

Hypertrophy also predisposes to myocardial ischemia¹⁷. This may explain why steers fed zilpaterol had significantly greater cardiac troponin I concentrations than controls, the latter having concentrations similar to those reported in healthy cows²². Intriguingly, the two steers with the greatest cardiac troponin I concentrations also had the greatest left ventricular hypertrophy. This may have been coincidental, but the research literature suggests otherwise. Left ventricular hypertrophy in humans is a strong predictor of death from cardiovascular disease⁶. Without histological evaluation of the myocardial tissue, however, we cannot say if the statistical difference observed was biologically relevant.

Myocardial injury has, to our knowledge, not been previously associated with zilpaterol in cattle. A recent study of 30-Angus steers found no histologic evidence of apoptosis associated with the βAA zilpaterol and ractopamine²³. Myocardial necrosis and fibrosis have, however, been reported in association with ßAA in other species^24,25. The myocardial injury observed in association with zilpaterol in our study could have been exacerbated by poor air quality since the inhalation of particulate matter may exacerbate cardiopulmonary injury induced by ßAA^26,27. This may, in part, explain the seasonal variation observed in mortality risk associated with zilpaterol hydrochloride⁹.

The health implications of diastolic dysfunction in cattle fed βAA may be extensive: diastolic dysfunction in humans increases the risk of pulmonary edema²⁸ and all-cause mortality^29,30. Given that the findings of our study suggest that β₂AA-induced left ventricular hypertrophy caused diastolic dysfunction, and that an increased in all-cause mortality has been associated with the feeding of βAA to cattle⁹, studies to evaluate the effect of ßAA on cardiac function and morphology are needed. Suitable echocardiographic measures of diastolic ventricular function include transmitral filling velocity, ventricular relaxation velocity, and pulmonary vein flow. Pulmonary arteriolar wedge pressures would provide a more accurate measure of left ventricular end-diastolic pressure than diastolic PAP. Balloon floatation catheters are superior to the saline-filled polyethylene tubing typically used for PAP measurement¹² because arteriolar occlusion is necessary for accurate wedge pressure measurement.

A limitation of our study design is that it was necessary to forfeit external validity to maintain internal validity. This allowed us to successfully address the aim of this study. To achieve internal validity, cattle were not randomized into treatment groups because, in the feedlot studied, the feeding of zilpaterol was at the discretion of the feedlot manager. Concerned that zilpaterol may increase the risk of death, particularly among cattle with a history of disease, the feedlot manager only fed zilpaterol to cattle in pens with a low incidence of morbidity and mortality. Given that respiratory disease predisposes cattle to heart failure³¹, any confounding, if present, should have biased the results towards the null. Large, randomized studies are necessary to validate our findings because our results cannot be extrapolated to other feedlots and the number of cattle studied was small.

In conclusion, our results raise concerns that, in the feedlot studied, zilpaterol hydrochloride predisposes cattle to cardiac disease. Healthy cattle fed the βAA zilpaterol hydrochloride had left ventricular hypertrophy that was positively associated with diastolic PAP and myocardial injury.

Data availability

All raw data underlying this study is available from Harvard Dataverse under a CC0 Public Domain Dedication: http://dx.doi.org/10.7910/DVN/4IKGIN³²

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Faculty Opinions recommended

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Author details Author details

¹ Department of Animal and Food Sciences, College of Agriculture and Natural Resources, Texas Tech University, Lubbock, TX, USA
² Integrated Livestock Management, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
³ Veterinary Diagnostic Laboratory, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA
⁴ Department of Pediatrics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA

Joseph M. Neary
Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing

Franklyn B. Garry
Roles: Conceptualization, Data Curation, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Supervision, Writing – Review & Editing

Daniel H. Gould
Roles: Data Curation, Investigation, Methodology, Project Administration, Writing – Review & Editing

Timothy N. Holt
Roles: Investigation, Methodology, Writing – Review & Editing

R. Dale Brown
Roles: Data Curation, Investigation, Project Administration, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (1)

version 1

Published: 26 Mar 2018, 7:399

https://doi.org/10.12688/f1000research.14313.1

Copyright

© 2018 Neary JM et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Neary JM, Garry FB, Gould DH et al. The beta-adrenergic agonist zilpaterol hydrochloride may predispose feedlot cattle to cardiac remodeling and dysfunction [version 1; peer review: 2 approved with reservations]. F1000Research 2018, 7:399 (https://doi.org/10.12688/f1000research.14313.1)

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Reviewer Report 16 Apr 2018

Harvey Morgan Scott, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.15575.r32894

I read the paper with great interest. The authors have uncovered a plausible mechanism by which increased mortality in late feeding period cattle might occur when fed a commercially approved beta-2-adrenergic agonist. The product was withdrawn from the U.S. feeding ... Continue reading

I read the paper with great interest. The authors have uncovered a plausible mechanism by which increased mortality in late feeding period cattle might occur when fed a commercially approved beta-2-adrenergic agonist. The product was withdrawn from the U.S. feeding market during the midst of this study in 2013, disrupting the study itself; however, the work that had occurred to that point provides a compelling glimpse into the potential pathology that was occurring when comparing matched treated and control animals. These are NOT cases and controls (in the traditional sense of a case-control study design); rather, the study is a frequency matched and closed cohort study with the matched control set drawn from non-treated pens of cattle concurrently to the 'exposed' animals (not: cases using epidemiological terminology) and the latter treated as determined by the feedlot manager. Thus, it is not an experimental design, it is an observational design. Also, it is not a case-control study, the closest design that fits is a cohort design (arguably, closed in that animals become at risk once the pen in which they reside is assigned to receive the beta-agonist and the control (unexposed) animals are determined to be in pens not receiving the BAA). An in vivo catheter-based arterial pressure assay was performed in the chutes, as well as a later post-mortem (at slaughter) matched comparison of ventricular wall mass versus carcass weight. The study became rather lop-sided/unbalanced during a particularly hot and stressful period which unfortunately coincided with the product withdrawal from the market. This has left some deficits in the potential statistical power of the study. Nevertheless, the findings are considerable and of interest and it is important that these results be presented with transparency and completeness. To this points I have some concerns (see below)

The authors should present the estimates for each of the parameters (plus, n=? animals and variances/standard errors) and for each of the groups. It is not enough to express the differences or ratios since the reader needs to do a comparison with expected norms to determine whether these reflect biological reality. For example, the diastolic pressures are not described (simply their differences) whereas the mean (overall, across diastolic and systolic) and also systolic by itself are presented openly. We need the diastolic pressures by group. We need to know the LVS mass, the carcass weights, etc and not just the ratios and differences between groups. Please also tabulate the cardiac troponin data. These data are intriguing but not easily understood in the narrative presentation. Why should we see the tabulated data for LVS and carcass weight? Because the BAA product increases carcass weight substantially and could affect the ratio independent of the septal mass (likely biasing it towards the null, I think...?; and, the reader needs to know). A carefully crafted table or two would make short work of this and greatly improve the paper and its readability.

Unless I have overlooked it, Figure 1 neglects to mention in the legend what the solid diamonds and clear circles represent.

The authors mention that 8 ZS and 8 CS (exposed and unexposed animals, respectively) were not included in statistical analysis due to previous bouts of respiratory disease. However, later these animals appeared to have been discussed despite this refrain (see paragraph 2 of the section under pulmonary arterial pressures)? I remain confused by this exclusion statement then the statistical comparisons based on pulmonary conditions?

Full disclosure: I have co-authored previous work identifying increased mortality in cattle fed BAAs (not just the B(2)AA studied in the article) and that work is cited in the paper (citation 9). That study was not mechanistic in nature; rather, it explored mortality experience across many hundreds of thousands of animals. The authors mention the 40-50% attributable fraction in that paper by Loneragan et al (2014), but that number applied also to the other commercially available beta-agonist (so both products, not just the products studied here). It is important to note that the attributable fraction applied only during the period in which the product was fed (last 21-28 days); in other words, earlier mortality due to respiratory disease and other calfhood diseases are not included in the denominator in Loneragan et al (2014) but the sentence almost implies that the 40-50% AF in that paper was across the entire feeding period (it is not). It is very important that we consider that animals dying in the late feeding period (where all the feed costs have accrued and the excessive protein waste is greatest) are accorded appropriate and clear mortality attribution.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Veterimary pathobiology, epidemiology, food animal production medicine, food safety, microbial ecology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Reviewer Report 03 Apr 2018

H. Kirk Hammond, VA San Diego Healthcare System, San Diego, CA, USA; Department of Medicine, University of California, San Diego, CA, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.15575.r32480

This is an interesting and unusual study that examines LV mass in steers after administration of zilpaterol (Z).

Problems
Background/Introduction

Were all animals on “hormone growth promotant” to increase growth

This is an interesting and unusual study that examines LV mass in steers after administration of zilpaterol (Z).

Problems
Background/Introduction

Were all animals on “hormone growth promotant” to increase growth rates/skeletal muscle mass?
- What hormone?
- Is this hormone the more likely cause of increased skeletal muscle mass, rather than Z? Need to sort this out in the intro.
- A possible flaw is that one cannot sort out what deleterious effects are due to the hormone vs Z - ideally a third group on neither hormone or Z would be required. Not asking you to re-do the study, but this confounding element needs discussion.

Methods

PA Pressures. Not clear how the pulmonary pressures were measured. Please include: anesthesia, body position, how the pressure calibrations were made (for example, “0” at what level of the body and in what position.
Statistics. I was frustrated that the authors did not simply provide the mean ±SD of each of the 2 groups with a simple Student’s t-test to examine for group differences.
- Please provide such data (and p values) for LV weight, LV/BW ratio, TnI, and pulmonary pressures (PAS, PAD.PA mean), HR

Results

The findings are: increased LV mass, and increased PA pressures (although a between-group simple comparison for significance is required to be certain of this; see #3). The TnI data are quite weak and likely showed no group difference and should be de-emphasized. If blood is available, CK-MB might provide helpful support if it shows a group difference.
The absence of histological examination of the heart is a major omission in this study and should be emphasized in the discussion.

Discussion

The findings (if confirmed, see point 3,4) are increased LV weight and increased pulmonary pressure. The demonstration of heart failure or diastolic dysfunction was not established, so the authors should be more circumspect on their confidence that the animals have diastolic dysfunction.
LV Assessment. Too bad that in-life echocardiography or diastolic arrest and measurement of LV wall thickness were not assessed. As it stands, we cannot be sure whether the LV mass increase was due to eccentric of concentric LVH, and whether there was a change in EF. This should be emphasized in the discussion.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Translational physiology, cardiovascular physiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

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Version 1 26 Mar 18	read	read

H. Kirk Hammond, VA San Diego Healthcare System, San Diego, USA; University of California, San Diego, USA
Harvey Morgan Scott, Texas A&M University, College Station, USA

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Reviewer Report

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16 Apr 2018 | for Version 1

Harvey Morgan Scott, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA

12 Views Cite this report Responses(0)

Approved With Reservations

I read the paper with great interest. The authors have uncovered a plausible mechanism by which increased mortality in late feeding period cattle might occur when fed a commercially approved beta-2-adrenergic agonist. The product was withdrawn from the U.S. feeding market during the midst of this study in 2013, disrupting the study itself; however, the work that had occurred to that point provides a compelling glimpse into the potential pathology that was occurring when comparing matched treated and control animals. These are NOT cases and controls (in the traditional sense of a case-control study design); rather, the study is a frequency matched and closed cohort study with the matched control set drawn from non-treated pens of cattle concurrently to the 'exposed' animals (not: cases using epidemiological terminology) and the latter treated as determined by the feedlot manager. Thus, it is not an experimental design, it is an observational design. Also, it is not a case-control study, the closest design that fits is a cohort design (arguably, closed in that animals become at risk once the pen in which they reside is assigned to receive the beta-agonist and the control (unexposed) animals are determined to be in pens not receiving the BAA). An in vivo catheter-based arterial pressure assay was performed in the chutes, as well as a later post-mortem (at slaughter) matched comparison of ventricular wall mass versus carcass weight. The study became rather lop-sided/unbalanced during a particularly hot and stressful period which unfortunately coincided with the product withdrawal from the market. This has left some deficits in the potential statistical power of the study. Nevertheless, the findings are considerable and of interest and it is important that these results be presented with transparency and completeness. To this points I have some concerns (see below)

The authors should present the estimates for each of the parameters (plus, n=? animals and variances/standard errors) and for each of the groups. It is not enough to express the differences or ratios since the reader needs to do a comparison with expected norms to determine whether these reflect biological reality. For example, the diastolic pressures are not described (simply their differences) whereas the mean (overall, across diastolic and systolic) and also systolic by itself are presented openly. We need the diastolic pressures by group. We need to know the LVS mass, the carcass weights, etc and not just the ratios and differences between groups. Please also tabulate the cardiac troponin data. These data are intriguing but not easily understood in the narrative presentation. Why should we see the tabulated data for LVS and carcass weight? Because the BAA product increases carcass weight substantially and could affect the ratio independent of the septal mass (likely biasing it towards the null, I think...?; and, the reader needs to know). A carefully crafted table or two would make short work of this and greatly improve the paper and its readability.

Unless I have overlooked it, Figure 1 neglects to mention in the legend what the solid diamonds and clear circles represent.

The authors mention that 8 ZS and 8 CS (exposed and unexposed animals, respectively) were not included in statistical analysis due to previous bouts of respiratory disease. However, later these animals appeared to have been discussed despite this refrain (see paragraph 2 of the section under pulmonary arterial pressures)? I remain confused by this exclusion statement then the statistical comparisons based on pulmonary conditions?

Full disclosure: I have co-authored previous work identifying increased mortality in cattle fed BAAs (not just the B(2)AA studied in the article) and that work is cited in the paper (citation 9). That study was not mechanistic in nature; rather, it explored mortality experience across many hundreds of thousands of animals. The authors mention the 40-50% attributable fraction in that paper by Loneragan et al (2014), but that number applied also to the other commercially available beta-agonist (so both products, not just the products studied here). It is important to note that the attributable fraction applied only during the period in which the product was fed (last 21-28 days); in other words, earlier mortality due to respiratory disease and other calfhood diseases are not included in the denominator in Loneragan et al (2014) but the sentence almost implies that the 40-50% AF in that paper was across the entire feeding period (it is not). It is very important that we consider that animals dying in the late feeding period (where all the feed costs have accrued and the excessive protein waste is greatest) are accorded appropriate and clear mortality attribution.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

Yes
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Veterimary pathobiology, epidemiology, food animal production medicine, food safety, microbial ecology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Respond to this report

Responses (0)

Back to all reports

Reviewer Report

17 Views

03 Apr 2018 | for Version 1

H. Kirk Hammond, VA San Diego Healthcare System, San Diego, CA, USA; Department of Medicine, University of California, San Diego, CA, USA

17 Views Cite this report Responses(0)

Approved With Reservations

This is an interesting and unusual study that examines LV mass in steers after administration of zilpaterol (Z).

Problems
Background/Introduction

Were all animals on “hormone growth promotant” to increase growth rates/skeletal muscle mass?
- What hormone?
- Is this hormone the more likely cause of increased skeletal muscle mass, rather than Z? Need to sort this out in the intro.
- A possible flaw is that one cannot sort out what deleterious effects are due to the hormone vs Z - ideally a third group on neither hormone or Z would be required. Not asking you to re-do the study, but this confounding element needs discussion.

Methods

PA Pressures. Not clear how the pulmonary pressures were measured. Please include: anesthesia, body position, how the pressure calibrations were made (for example, “0” at what level of the body and in what position.
Statistics. I was frustrated that the authors did not simply provide the mean ±SD of each of the 2 groups with a simple Student’s t-test to examine for group differences.
- Please provide such data (and p values) for LV weight, LV/BW ratio, TnI, and pulmonary pressures (PAS, PAD.PA mean), HR

Results

The findings are: increased LV mass, and increased PA pressures (although a between-group simple comparison for significance is required to be certain of this; see #3). The TnI data are quite weak and likely showed no group difference and should be de-emphasized. If blood is available, CK-MB might provide helpful support if it shows a group difference.
The absence of histological examination of the heart is a major omission in this study and should be emphasized in the discussion.

Discussion

The findings (if confirmed, see point 3,4) are increased LV weight and increased pulmonary pressure. The demonstration of heart failure or diastolic dysfunction was not established, so the authors should be more circumspect on their confidence that the animals have diastolic dysfunction.
LV Assessment. Too bad that in-life echocardiography or diastolic arrest and measurement of LV wall thickness were not assessed. As it stands, we cannot be sure whether the LV mass increase was due to eccentric of concentric LVH, and whether there was a change in EF. This should be emphasized in the discussion.

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

I cannot comment. A qualified statistician is required.
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Translational physiology, cardiovascular physiology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Respond to this report

Responses (0)

[1] 1. Health and Human Services, F. a. D. A. w: Freedom of information summary. Original new animal drug application. NADA 141– 221 ractopamine hydrochloride (OPTAFLEXX 45) type A medicated article for beef cattle. 2003. Reference Source

[2] 2. Health and Human Services, F. a. D. A. w: Freedom of information summary. Original new animal drug application. NADA 141– 258 ZILMAX (zilpaterol hydrochloride) type A medicated article for cattle fed in confinement for slaughter. 2006.

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[32] 32. Neary J: Raw data: Growth promotion with the beta-adrenergic agonist zilpaterol hydrochloride may predispose feedlot cattle to cardiac remodeling and dysfunction. Harvard Dataverse, V1, UNF:6:tWTwcydm4r5SFm+ILXs0Vw==. 2018. Data Source

The beta-adrenergic agonist zilpaterol hydrochloride may predispose feedlot cattle to cardiac remodeling and dysfunction

Abstract

Keywords

Introduction

Methods

Ethical considerations

Study site and sampling

Table 1. The number of cattle tested according to the date of testing in the year 2013.

Pulmonary arterial pressure (PAP) measurement

Blood analysis

Hot carcass weight (HCW) and ventricular weights

Statistical analyses

Results

Pulmonary arterial pressures

Cardiac hypertrophy

Figure 1. The relationship between A) diastolic pulmonary arterial pressure (PAP) and B) plasma cardiac troponin I with mass of the left ventricle plus inter-ventricular septum (LVS) per 100 kg of hot carcass weight (HCW).

Cardiac troponin I (cTnI)

Discussion

Data availability

Competing interests

Grant information

References

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