JACC: Heart Failure 2014 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 2, No. 1, 2014 ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2013.09.005
Cardiac Size and Sex-Matching in Heart Transplantation Size Matters in Matters of Sex and the Heart Robert M. Reed, MD,* Giora Netzer, MD, MSCE,*y Lawrence Hunsicker, MD,z Braxton D. Mitchell, PHD,xjj Keshava Rajagopal, MD, PHD,{ Steven Scharf, MD, PHD,* Michael Eberlein, MD, PHD# Baltimore, Maryland; and Iowa City, Iowa
JACC: HEART FAILURE CME This article has been selected as the month’s JACC: Heart Failure CME activity. Accreditation and Designation Statement The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Method of Participation and Receipt of CME Certificate To obtain credit for JACC: Heart Failure CME, you must: 1. Be an ACC member or JACC subscriber. 2. Carefully read the CME-designated article available online and in this issue of the journal. 3. Answer the post-test questions. At least 2 out of the 3 questions provided must be answered correctly to obtain CME credit. 4. Complete a brief evaluation. 5. Claim your CME credit and receive your certificate electronically by following the instructions given at the conclusion of the activity.
From the *Division of Pulmonary and Critical Care Medicine University of Maryland School of Medicine, Baltimore, Maryland; yDivision of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland; zDivision of Nephrology, University of Iowa School of Medicine, Iowa City, Iowa; xDivision of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland; jjDepartment of Veterans Affairs and Veterans Affairs Medical Center Baltimore Geriatric Research Education and Clinical Center (GRECC), Baltimore, Maryland; {Division of Cardiothoracic Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and the #Division of Pulmonary and Critical Care Medicine, University of Iowa School of Medicine, Iowa City, Iowa. This
CME Objective for This Article: After reading this article, the reader should understand: 1) the current data regarding heart size and gender matching in cardiac transplantation; 2) strategies to optimize donor-recipient matching to improve patient outcomes; and 3) the implications of these data related to organ allocation. CME Editor Disclosure: Deputy Managing Editor Mona Fiuzat, PharmD, FACC, reports that she has equity interest or stock options in ARCA Biopharma, consults for CCA, and receives research support from ResMed, GE Healthcare, Gilead, Critical Diagnostics, BG Medicine, Otsuka, Astellas, and Roche Diagnostics. Author Disclosures: Dr. Reed is funded in part by the Alpha-1 Antitrypsin Foundation/Chest Foundation, as well as the Flight Attendant Medical Research Institute. Dr. Netzer is funded in part by National Institutes of Health (NIH) 5K12RR023250-03. Dr. Mitchell is funded in part by the Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore GRECC. Dr. Scharf is funded in part by National Heart, Lung, and Blood Institute HL074441. All other authors report that they have no relationships relevant to the contents of this paper to disclose. Medium of Participation: Print (article only); online (article and quiz) CME Term of Approval: Issue date: February 2014 Expiration date: January 31, 2015
work was supported in part by Health Resources and Services Administration contract 234-2005-370011C. Dr. Reed is funded in part by the Alpha-1 Antitrypsin Foundation/Chest Foundation as well as the Flight Attendant Medical Research Institute. Dr. Netzer is funded in part by National Institutes of Health (NIH) 5K12RR023250-03. Dr. Mitchell is funded in part by the Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore GRECC. Dr. Scharf is funded in part by National Heart, Lung, and Blood Institute HL074441. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received August 1, 2013; revised manuscript received August 28, 2013, accepted September 5, 2013.
74
Reed et al. Size and Sex Matching in Heart Transplantation
JACC: Heart Failure Vol. 2, No. 1, 2014 February 2014:73–83
Cardiac Size and Sex-Matching in Heart Transplantation Size Matters in Matters of Sex and the Heart Objective
This study evaluated whether worsened outcomes in sex mismatch are related to mismatch of organ size in heart transplantation.
Background
Sizing for organ allocation in heart transplantation currently incorporates only body weight differences between the donor and recipient. Weight correlates poorly to cardiac size, and donor–recipient weight differences are not associated with differential survival. Heart size correlates with sex, and donor–recipient sex mismatch conveys worse-than-expected outcomes.
Methods
We performed a retrospective cohort study of 31,634 donor–recipient adult heart transplant pairings from the United Network for Organ Sharing transplantation registry. We used predictive models to calculate the predicted total heart mass (pHM) for recipient and donor pairs. We assessed organ size mismatch by calculating the percent difference between the donor and recipient pHM as [(pHMrecipient – pHMdonor)/(pHMrecipient)]*100.
Results
The most-undersized pHM septile demonstrated higher mortality during the first year post-transplantation (hazard ratio [HR]: 1.27; p < 0.001), which remained robust in adjusted models (HR: 1.25; p ¼ 0.03). Survival did not vary across septiles of weight differences. On univariate analysis, sex mismatch was associated with higher mortality in male patients, but not in female patients. Controlling for differences in pHM reversed these associations. Adjusted models demonstrated worse survival associated with sex mismatch in female patients (1-year HR: 1.28; p ¼ 0.02) but no difference in male patients (1-year HR, 1.00; p ¼ 1.0).
Conclusions
Differences in donor–recipient pHM modulated the survival associated with donor–recipient sex mismatch and identified donor heart undersizing as an otherwise occult and potentially preventable cause of mortality following orthotopic heart transplantation. (J Am Coll Cardiol HF 2014;2:73–83) ª 2014 by the American College of Cardiology Foundation
Over 3,700 people worldwide undergo heart transplantation each year (1). Organ allocation for heart transplantation currently incorporates only body weight into sizing considerations. This sizing method assumes a direct correlation between body weight and cardiac size. It functions poorly to predict outcomes (2,3). Heart size varies by sex, and studies of heart transplantation have consistently observed reduced survival associated with donor organ sex mismatch, particularly for male recipients of female organs (3–9). Recent studies utilizing cardiac magnetic resonance have provided prediction models of cardiac mass that incorporate height, weight, age, and sex (10,11). These prediction models provide estimates of heart size that differ significantly from estimates using body weight alone. For example, the predicted heart masses (pHM) of a man and a woman both 55 years of age, 80 kg in weight, and 1.75 m tall yield a difference in pHM of 19%. Applying these measures again, a man would have to weigh 20 kg (25%) less than an otherwise similar woman to yield an equivalent pHM. It is therefore likely that the current practice of matching donor organs to recipients based on body weight differences fails to discriminate substantial size mismatches. Using the United Network of Organ Sharing database of heart transplantation, we performed a retrospective cohort study to examine the relationship between size matching and clinical outcomes and to ascertain whether mismatched size accounts for differential survival with sex-mismatched organs. Methods Data source. We analyzed data from adult (age 18 years) first-time heart transplant recipients who underwent
transplantation between October 1989 and June 2011. Data were extracted from the Standard Transplant Analysis and Research files, provided by the United Network of Organ Sharing. These files were compiled from individual centers and entered by data entry personnel using an electronic system with built-in data validation processes. This study was approved by the institutional review board at the University of Maryland, Baltimore, Maryland. Study design. Our primary interest was in heart size matching. Size was evaluated using pHM values generated by combining right and left ventricular mass. We used previously published equations for left ventricular and right ventricular mass (10,11), as follows: ½1 Predicted left ventricular mass g
¼ a $ Height0:54 ðmÞ $ Weight0:61 kg
where a ¼ 6.82 for women and 8.25 for men; and ½2 Predicted right ventricular mass g ¼ a $ Age0:32 years $ Height1:135 ðmÞ $ Weight0:315 kg
where a ¼ 10.59 for women and 11.25 for men. The difference in pHM was calculated according to the percent difference in pHM between the donor heart and the recipient heart, which we defined as ½ðpHMrecipient pHMdonor Þ=ðpHMrecipient Þ$100. To facilitate comparison with the conventional standard of size matching, percent differences in body weight were calculated similarly. Patients missing the information needed to
JACC: Heart Failure Vol. 2, No. 1, 2014 February 2014:73–83
calculate the percent difference in pHM were not included in analysis. The data were inspected for outliers and implausible values. These were recoded as null datapoints. Values changed to null included: weight >130 or 40 or 10 l/min, creatinine >5 mg/dl, height >210 or 100 mg/dl, and differences in weight matching between donor and recipient >100% or
Vol. 2, No. 1, 2014 ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2013.09.005
Cardiac Size and Sex-Matching in Heart Transplantation Size Matters in Matters of Sex and the Heart Robert M. Reed, MD,* Giora Netzer, MD, MSCE,*y Lawrence Hunsicker, MD,z Braxton D. Mitchell, PHD,xjj Keshava Rajagopal, MD, PHD,{ Steven Scharf, MD, PHD,* Michael Eberlein, MD, PHD# Baltimore, Maryland; and Iowa City, Iowa
JACC: HEART FAILURE CME This article has been selected as the month’s JACC: Heart Failure CME activity. Accreditation and Designation Statement The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Method of Participation and Receipt of CME Certificate To obtain credit for JACC: Heart Failure CME, you must: 1. Be an ACC member or JACC subscriber. 2. Carefully read the CME-designated article available online and in this issue of the journal. 3. Answer the post-test questions. At least 2 out of the 3 questions provided must be answered correctly to obtain CME credit. 4. Complete a brief evaluation. 5. Claim your CME credit and receive your certificate electronically by following the instructions given at the conclusion of the activity.
From the *Division of Pulmonary and Critical Care Medicine University of Maryland School of Medicine, Baltimore, Maryland; yDivision of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland; zDivision of Nephrology, University of Iowa School of Medicine, Iowa City, Iowa; xDivision of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland; jjDepartment of Veterans Affairs and Veterans Affairs Medical Center Baltimore Geriatric Research Education and Clinical Center (GRECC), Baltimore, Maryland; {Division of Cardiothoracic Surgery, University of Maryland School of Medicine, Baltimore, Maryland; and the #Division of Pulmonary and Critical Care Medicine, University of Iowa School of Medicine, Iowa City, Iowa. This
CME Objective for This Article: After reading this article, the reader should understand: 1) the current data regarding heart size and gender matching in cardiac transplantation; 2) strategies to optimize donor-recipient matching to improve patient outcomes; and 3) the implications of these data related to organ allocation. CME Editor Disclosure: Deputy Managing Editor Mona Fiuzat, PharmD, FACC, reports that she has equity interest or stock options in ARCA Biopharma, consults for CCA, and receives research support from ResMed, GE Healthcare, Gilead, Critical Diagnostics, BG Medicine, Otsuka, Astellas, and Roche Diagnostics. Author Disclosures: Dr. Reed is funded in part by the Alpha-1 Antitrypsin Foundation/Chest Foundation, as well as the Flight Attendant Medical Research Institute. Dr. Netzer is funded in part by National Institutes of Health (NIH) 5K12RR023250-03. Dr. Mitchell is funded in part by the Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore GRECC. Dr. Scharf is funded in part by National Heart, Lung, and Blood Institute HL074441. All other authors report that they have no relationships relevant to the contents of this paper to disclose. Medium of Participation: Print (article only); online (article and quiz) CME Term of Approval: Issue date: February 2014 Expiration date: January 31, 2015
work was supported in part by Health Resources and Services Administration contract 234-2005-370011C. Dr. Reed is funded in part by the Alpha-1 Antitrypsin Foundation/Chest Foundation as well as the Flight Attendant Medical Research Institute. Dr. Netzer is funded in part by National Institutes of Health (NIH) 5K12RR023250-03. Dr. Mitchell is funded in part by the Department of Veterans Affairs and Veterans Affairs Medical Center Baltimore GRECC. Dr. Scharf is funded in part by National Heart, Lung, and Blood Institute HL074441. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received August 1, 2013; revised manuscript received August 28, 2013, accepted September 5, 2013.
74
Reed et al. Size and Sex Matching in Heart Transplantation
JACC: Heart Failure Vol. 2, No. 1, 2014 February 2014:73–83
Cardiac Size and Sex-Matching in Heart Transplantation Size Matters in Matters of Sex and the Heart Objective
This study evaluated whether worsened outcomes in sex mismatch are related to mismatch of organ size in heart transplantation.
Background
Sizing for organ allocation in heart transplantation currently incorporates only body weight differences between the donor and recipient. Weight correlates poorly to cardiac size, and donor–recipient weight differences are not associated with differential survival. Heart size correlates with sex, and donor–recipient sex mismatch conveys worse-than-expected outcomes.
Methods
We performed a retrospective cohort study of 31,634 donor–recipient adult heart transplant pairings from the United Network for Organ Sharing transplantation registry. We used predictive models to calculate the predicted total heart mass (pHM) for recipient and donor pairs. We assessed organ size mismatch by calculating the percent difference between the donor and recipient pHM as [(pHMrecipient – pHMdonor)/(pHMrecipient)]*100.
Results
The most-undersized pHM septile demonstrated higher mortality during the first year post-transplantation (hazard ratio [HR]: 1.27; p < 0.001), which remained robust in adjusted models (HR: 1.25; p ¼ 0.03). Survival did not vary across septiles of weight differences. On univariate analysis, sex mismatch was associated with higher mortality in male patients, but not in female patients. Controlling for differences in pHM reversed these associations. Adjusted models demonstrated worse survival associated with sex mismatch in female patients (1-year HR: 1.28; p ¼ 0.02) but no difference in male patients (1-year HR, 1.00; p ¼ 1.0).
Conclusions
Differences in donor–recipient pHM modulated the survival associated with donor–recipient sex mismatch and identified donor heart undersizing as an otherwise occult and potentially preventable cause of mortality following orthotopic heart transplantation. (J Am Coll Cardiol HF 2014;2:73–83) ª 2014 by the American College of Cardiology Foundation
Over 3,700 people worldwide undergo heart transplantation each year (1). Organ allocation for heart transplantation currently incorporates only body weight into sizing considerations. This sizing method assumes a direct correlation between body weight and cardiac size. It functions poorly to predict outcomes (2,3). Heart size varies by sex, and studies of heart transplantation have consistently observed reduced survival associated with donor organ sex mismatch, particularly for male recipients of female organs (3–9). Recent studies utilizing cardiac magnetic resonance have provided prediction models of cardiac mass that incorporate height, weight, age, and sex (10,11). These prediction models provide estimates of heart size that differ significantly from estimates using body weight alone. For example, the predicted heart masses (pHM) of a man and a woman both 55 years of age, 80 kg in weight, and 1.75 m tall yield a difference in pHM of 19%. Applying these measures again, a man would have to weigh 20 kg (25%) less than an otherwise similar woman to yield an equivalent pHM. It is therefore likely that the current practice of matching donor organs to recipients based on body weight differences fails to discriminate substantial size mismatches. Using the United Network of Organ Sharing database of heart transplantation, we performed a retrospective cohort study to examine the relationship between size matching and clinical outcomes and to ascertain whether mismatched size accounts for differential survival with sex-mismatched organs. Methods Data source. We analyzed data from adult (age 18 years) first-time heart transplant recipients who underwent
transplantation between October 1989 and June 2011. Data were extracted from the Standard Transplant Analysis and Research files, provided by the United Network of Organ Sharing. These files were compiled from individual centers and entered by data entry personnel using an electronic system with built-in data validation processes. This study was approved by the institutional review board at the University of Maryland, Baltimore, Maryland. Study design. Our primary interest was in heart size matching. Size was evaluated using pHM values generated by combining right and left ventricular mass. We used previously published equations for left ventricular and right ventricular mass (10,11), as follows: ½1 Predicted left ventricular mass g
¼ a $ Height0:54 ðmÞ $ Weight0:61 kg
where a ¼ 6.82 for women and 8.25 for men; and ½2 Predicted right ventricular mass g ¼ a $ Age0:32 years $ Height1:135 ðmÞ $ Weight0:315 kg
where a ¼ 10.59 for women and 11.25 for men. The difference in pHM was calculated according to the percent difference in pHM between the donor heart and the recipient heart, which we defined as ½ðpHMrecipient pHMdonor Þ=ðpHMrecipient Þ$100. To facilitate comparison with the conventional standard of size matching, percent differences in body weight were calculated similarly. Patients missing the information needed to
JACC: Heart Failure Vol. 2, No. 1, 2014 February 2014:73–83
calculate the percent difference in pHM were not included in analysis. The data were inspected for outliers and implausible values. These were recoded as null datapoints. Values changed to null included: weight >130 or 40 or 10 l/min, creatinine >5 mg/dl, height >210 or 100 mg/dl, and differences in weight matching between donor and recipient >100% or
