1. Lancet. 2024 Aug 17;404(10453):670-682. doi: 10.1016/S0140-6736(24)01078-X.

Hypothermic oxygenated perfusion of the donor heart in heart transplantation:

the short-term outcome from a randomised, controlled, open-label, multicentre
clinical trial.

Rega F(1), Lebreton G(2), Para M(3), Michel S(4), Schramm R(5), Begot E(2),
Vandendriessche K(6), Kamla C(4), Gerosa G(7), Berman M(8), Boeken U(9), Clark
S(10), Ranasinghe A(11), Ius F(12), Forteza A(13), Pivodic A(14), Hennig F(15),
Guenther S(5), Zuckermann A(16), Knosalla C(15), Dellgren G(17), Wallinder
A(18); NIHP2019 investigators.

Collaborators: Van Cleemput J(19), Degezelle K(6), Wert L(20), Yeter R(20),
Lichtenber A(9), Aubin H(9), Görler A(12), Freyt S(12), McDiamud A(21),
Jungschleger J(21), Mukadam M(22), Turner P(22), Mullen R(23), Hernández F(24),
Ospina V(13), Jonsson K(17), Ternström L(17), Al Kalbany H(2), Djavidi N(2),
Fabozzo A(7), Pradegan N(7), Aliabadi-Zuckermann A(16), Osorio E(16).

Author information:
(1)Department of Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium.
Electronic address: [email protected].
(2)Cardiac Surgery Department, Pitié-Salpétrière Hospital, APHP, Sorbonne
University, Paris, France.
(3)Department of Cardiovascular Surgery and Transplantation, Bichat Hospital,
Université Paris Cité, Paris, France.
(4)Clinic of Cardiac Surgery, Ludwig-Maximilians-University of Munich, Munich,
Germany; Munich Heart Alliance, German Center for Cardiovascular Research,
Munich, Germany.
(5)Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Center
North Rhine Westfalia, Ruhr-University Bochum, Bad Oeynhausen, Germany.
(6)Department of Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium.
(7)Department of Cardiac, Thoracic, Vascular Sciences and Public Health,
University of Padua, Padua, Italy.
(8)Cardiothoracic Surgery, Royal Papworth Hospital NHS Foundation Trust,
Cambridge, UK.
(9)Department of Cardiac Surgery, Medical Faculty, Heinrich Heine University,
Duesseldorf, Germany.
(10)Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne, UK.
(11)Cardiac Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham
NHS Trust, Birmingham, UK.
(12)Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover
Medical School, Hannover, Germany.
(13)Department of Cardiac Surgery, Puerta de Hierro Majadahonda University
Hospital, Madrid, Spain.
(14)APNC Sweden, Molndal, Sweden.
(15)Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der
Charité, Berlin, Germany; Charité-Universitätsmedizin Berlin, corporate member
of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany;
German Center for Cardiovascular Research, Berlin, Germany.
(16)Department of Cardiac Surgery, Medical University of Vienna, Vienna,
Austria.
(17)Department of Cardiothoracic Surgery, Sahlgrenska University Hospital,
Gothenburg, Sweden.
(18)XVIVO Perfusion, Gothenburg, Sweden.
(19)Department of Cardiology, University Hospitals Leuven, Leuven, Belgium.
(20)Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der
Charité (DHZC), Berlin, Germany.
(21)Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne, United
Kingdom.
(22)Department of Cardiac, Thoracic, Vascular Sciences and Public Health, Queen
Elizabeth Hospital, University Hospitals Birmingham NHS Trust, Birmingham,
United Kingdom.
(23)Cardiothoracic Surgery, Royal Papworth Hospital NHS Foundation Trust,
Cambridge, United Kingdom.
(24)Department of Cardiology, Puerta de Hierro Majadahonda University Hospital,
Madrid, Spain.

Erratum in
Lancet. 2024 Oct 26;404(10463):1644. doi: 10.1016/S0140-6736(24)02313-4.

BACKGROUND: Static cold storage (SCS) remains the gold standard for preserving
donor hearts before transplantation but is associated with ischaemia, anaerobic
metabolism, and organ injuries, leading to patient morbidity and mortality. We
aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion
(HOPE) of the donor heart is safe and superior compared with SCS.
METHODS: We performed a multinational, multicentre, randomised, controlled,
open-label clinical trial with a superiority design at 15 transplant centres
across eight European countries. Adult candidates for heart transplantation were
eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age
18-70 years with no previous sternotomy and donation after brain death. In the
treatment group, the preservation protocol involved the use of a portable
machine perfusion system ensuring HOPE of the resting donor heart. The donor
hearts in the control group underwent ischaemic SCS according to standard
practices. The primary outcome was time to first event of a composite of either
cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the
left ventricle, PGD of the right ventricle, acute cellular rejection at least
grade 2R, or graft failure (with use of mechanical circulatory support or
re-transplantation) within 30 days after transplantation. We included all
patients who were randomly assigned, fulfilled inclusion and exclusion criteria,
and received a transplant in the primary analysis and all patients who were
randomly assigned and received a transplant in the safety analyses. This trial
was registered with ClicalTrials.gov (NCT03991923) and is ongoing.
FINDINGS: A total of 229 patients were enrolled between Nov 25, 2020, and May
19, 2023. The primary analysis population included 204 patients who received a
transplant. There were no patients who received a transplant lost to follow-up.
All 100 donor hearts preserved with HOPE were transplantable after perfusion.
The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE
group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk
reduction of 44% (hazard ratio 0·56; 95% CI 0·32-0·99; log-rank test p=0·059).
PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29
(28%) in the SCS group (risk ratio 0·39; 95% CI 0·20-0·73). In the HOPE group,
63 (65%) patients had a reported serious adverse event (158 events) versus 87
(70%; 222 events) in the SCS group. Major adverse cardiac transplant events were
reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio
0·56; 95% CI 0·34-0·92).
INTERPRETATION: Although there was not a significant difference in the primary
endpoint, the 44% risk reduction associated with HOPE was suggested to be a
clinically meaningful benefit. Post-transplant complications, measured as major
adverse cardiac transplant events, were reduced. Analysis of secondary outcomes
suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE
in donor heart preservation addresses the existing challenges associated with
graft preservation and the increasing complexity of donors and heart
transplantation recipients. Future investigation will help to further elucidate
the benefit of HOPE.
FUNDING: XVIVO Perfusion.

Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and
data mining, AI training, and similar technologies.
DOI: 10.1016/S0140-6736(24)01078-X
PMID: 39153817 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of interests The sponsor provided

the investigational devices and financial support for trial-specific
investigational site costs to all participating centres. FR reports
institutional research grants from XVIVO outside of the submitted work and
receiving speakers fees from Atricure. GL reports receiving study materials from
XVIVO as investigator in another clinical trial. SM reports research grants from
German Center for Lung Research and German Research Foundation and honoraria
from Berlin Heart. GD reports research grants from Astellas and Abbot and being
a programme chair for ISHLT and a board member of XVIVO. AW is employed by the
trial sponsor and may retain stock or stock options. All other authors declare
no competing interests.

2. JACC Heart Fail. 2024 Mar;12(3):438-447. doi: 10.1016/j.jchf.2023.11.015. Epub

2024 Jan 24.

Increasing Utilization of Extended Criteria Donor Hearts for Transplantation:

The OCS Heart EXPAND Trial.

Schroder JN(1), Patel CB(2), DeVore AD(2), Casalinova S(2), Koomalsingh KJ(3),
Shah AS(4), Anyanwu AC(5), D'Alessandro DA(6), Mudy K(7), Sun B(7), Strueber
M(8), Khaghani A(9), Shudo Y(10), Esmailian F(11), Liao K(12), Pagani FD(13),
Silvestry S(14), Wang IW(15), Salerno CT(16), Absi TS(4), Madsen JC(6), Mancini
D(5), Fiedler AG(17), Milano CA(2), Smith JW(17).

Author information:
(1)Duke University Hospital, Durham, North Carolina, USA. Electronic address:
[email protected].
(2)Duke University Hospital, Durham, North Carolina, USA.
(3)University of Washington Medical Center, Seattle, Washington, USA.
(4)Vanderbilt University Medical Center, Nashville, Tennessee, USA.
(5)Icahn School of Medicine at Mount Sinai, New York, New York, USA.
(6)Massachusetts General Hospital, Boston, Massachusetts, USA.
(7)Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis,
Minnesota, USA.
(8)Baptist Medical Group, Memphis, Tennessee, USA.
(9)Queen Mary University of London, London, England.
(10)Stanford University Medical Center, Stanford, California, USA.
(11)Cedars-Sinai Medical Center, Los Angeles, California, USA.
(12)Baylor College of Medicine, Houston, Texas, USA.
(13)University of Michigan Medical Center, Ann Arbor, Michigan, USA.
(14)Advent Health, Orlando, Florida, USA.
(15)Memorial Healthcare System, Hollywood, Florida, USA.
(16)University of Chicago Medicine, Chicago, Illinois, USA.
(17)University of California-San Francisco, San Francisco, California, USA.

BACKGROUND: Extended criteria donor (ECD) hearts available with donation after
brain death (DBD) are underutilized for transplantation due to limitations of
cold storage.
OBJECTIVES: This study evaluated use of an extracorporeal perfusion system on
donor heart utilization and post-transplant outcomes in ECD DBD hearts.
METHODS: In this prospective, single-arm, multicenter study, adult heart
transplant recipients received ECD hearts using an extracorporeal perfusion
system if hearts met study criteria. The primary outcome was a composite of
30-day survival and absence of severe primary graft dysfunction (PGD). Secondary
outcomes were donor heart utilization rate, 30-day survival, and incidence of
severe PGD. The safety outcome was the mean number of heart graft-related
serious adverse events within 30 days. Additional outcomes included survival
through 2 years benchmarked to concurrent nonrandomized control subjects.
RESULTS: A total of 173 ECD DBD hearts were perfused; 150 (87%) were
successfully transplanted; 23 (13%) did not meet study transplantation criteria.
At 30 days, 92% of patients had survived and had no severe PGD. The 30-day
survival was 97%, and the incidence of severe PGD was 6.7%. The mean number of
heart graft-related serious adverse events within 30 days was 0.17 (95% CI:
0.11-0.23). Patient survival was 93%, 89%, and 86% at 6, 12, and 24 months,
respectively, and was comparable with concurrent nonrandomized control subjects.
CONCLUSIONS: Use of an extracorporeal perfusion system resulted in successfully
transplanting 87% of donor hearts with excellent patient survival to 2 years
post-transplant and low rates of severe PGD. The ability to safely use ECD DBD
hearts could substantially increase the number of heart transplants and expand
access to patients in need. (International EXPAND Heart Pivotal Trial
[EXPANDHeart]; NCT02323321; Heart EXPAND Continued Access Protocol;
NCT03835754).

Copyright © 2024 American College of Cardiology Foundation. Published by

Elsevier Inc. All rights reserved.

DOI: 10.1016/j.jchf.2023.11.015
PMID: 38276933 [Indexed for MEDLINE]

Conflict of interest statement: Funding Support and Author Disclosures The study
was funded by TransMedics Inc. Dr Schroder has received research funding paid to
his institution from TransMedics. Dr DeVore has received research funding
through his institution from the American Heart Association; Biofourmis;
Bodyport; Cytokinetics; American Regent Inc; The National Heart, Lung, and Blood
Institute; Novartis; and Story Health; consulting fees and/or honoraria from
Abiomed, AstraZeneca, Cardionomic, InnaMed, LivaNova, Natera, Novartis,
Procyrion, Story Health, Vifor, and Zoll; and nonfinancial support from Abbott
for educational and research activities. Dr Silvestry has received research
funding from Abbott, Abiomed, and Medtronic. Dr Milano has received research
funding from TransMedics. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose.

3. N Engl J Med. 2023 Jun 8;388(23):2121-2131. doi: 10.1056/NEJMoa2212438.

Transplantation Outcomes with Donor Hearts after Circulatory Death.

Schroder JN(1), Patel CB(1), DeVore AD(1), Bryner BS(1), Casalinova S(1), Shah
A(1), Smith JW(1), Fiedler AG(1), Daneshmand M(1), Silvestry S(1), Geirsson
A(1), Pretorius V(1), Joyce DL(1), Um JY(1), Esmailian F(1), Takeda K(1), Mudy
K(1), Shudo Y(1), Salerno CT(1), Pham SM(1), Goldstein DJ(1), Philpott J(1),
Dunning J(1), Lozonschi L(1), Couper GS(1), Mallidi HR(1), Givertz MM(1), Pham
DT(1), Shaffer AW(1), Kai M(1), Quader MA(1), Absi T(1), Attia TS(1), Shukrallah
B(1), Sun BC(1), Farr M(1), Mehra MR(1), Madsen JC(1), Milano CA(1),
D'Alessandro DA(1).

Author information:
(1)From Duke University Medical Center, Durham, NC (J.N.S., C.B.P., A.D.D.,
S.C., C.A.M.); Northwestern University (B.S.B., D.T.P.) and the University of
Chicago (C.T.S.) - both in Chicago; Vanderbilt University Medical Center,
Nashville (A.S., T.A.); University of Wisconsin Hospital and Clinics, Madison
(J.W.S.), and the Medical College of Wisconsin, Milwaukee (D.L.J.); the
University of California, San Francisco, San Francisco (A.G.F.), the University
of California, San Diego, La Jolla (V.P.), Cedars-Sinai Medical Center, Los
Angeles (F.E.), and Stanford University Medical Center, Stanford (Y.S.) - all in
California; Emory University Hospital, Atlanta (M.D., T.S.A.); Advent Health,
Orlando (S.S.), Mayo Clinic, Jacksonville (S.M.P.), and Tampa General Hospital,
Tampa (J.D., L.L.) - all in Florida; Yale School of Medicine, New Haven, CT
(A.G.); Nebraska Medical Center, Omaha (J.Y.U.); Columbia University Medical
Center, New York (K.T.), Montefiore Medical Center, Bronx (D.J.G.), and
Westchester Medical Center, Valhalla (M.K.) - all in New York; Minneapolis Heart
Institute Foundation (K.M., B.S., B.C.S.) and the University of Minnesota
Medical Center (A.W.S.) - both in Minneapolis; Sentara Norfolk General Hospital,
Norfolk (J.P.), and Virginia Commonwealth University, Richmond (M.A.Q.) - both
in Virginia; Tufts Medical Center (G.S.C.), Brigham and Women's Hospital
(H.R.M., M.M.G., M.R.M.), and Massachusetts General Hospital (J.C.M., D.A.D.) -
all in Boston; and the University of Texas Southwestern Medical Center, Dallas
(M.F.).

Comment in
Nat Cardiovasc Res. 2023 Jul;2(7):603. doi: 10.1038/s44161-023-00307-w.

BACKGROUND: Data showing the efficacy and safety of the transplantation of

hearts obtained from donors after circulatory death as compared with hearts
obtained from donors after brain death are limited.
METHODS: We conducted a randomized, noninferiority trial in which adult
candidates for heart transplantation were assigned in a 3:1 ratio to receive a
heart after the circulatory death of the donor or a heart from a donor after
brain death if that heart was available first (circulatory-death group) or to
receive only a heart that had been preserved with the use of traditional cold
storage after the brain death of the donor (brain-death group). The primary end
point was the risk-adjusted survival at 6 months in the as-treated
circulatory-death group as compared with the brain-death group. The primary
safety end point was serious adverse events associated with the heart graft at
30 days after transplantation.
RESULTS: A total of 180 patients underwent transplantation; 90 (assigned to the
circulatory-death group) received a heart donated after circulatory death and 90
(regardless of group assignment) received a heart donated after brain death. A
total of 166 transplant recipients were included in the as-treated primary
analysis (80 who received a heart from a circulatory-death donor and 86 who
received a heart from a brain-death donor). The risk-adjusted 6-month survival
in the as-treated population was 94% (95% confidence interval [CI], 88 to 99)
among recipients of a heart from a circulatory-death donor, as compared with 90%
(95% CI, 84 to 97) among recipients of a heart from a brain-death donor
(least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001
for noninferiority [margin, 20 percentage points]). There were no substantial
between-group differences in the mean per-patient number of serious adverse
events associated with the heart graft at 30 days after transplantation.
CONCLUSIONS: In this trial, risk-adjusted survival at 6 months after
transplantation with a donor heart that had been reanimated and assessed with
the use of extracorporeal nonischemic perfusion after circulatory death was not
inferior to that after standard-care transplantation with a donor heart that had
been preserved with the use of cold storage after brain death. (Funded by
TransMedics; ClinicalTrials.gov number, NCT03831048.).

Copyright © 2023 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2212438
PMID: 37285526 [Indexed for MEDLINE]

4. BMJ Open. 2023 Dec 28;13(12):e073729. doi: 10.1136/bmjopen-2023-073729.

Non-ischaemic preservation of the donor heart in heart transplantation: protocol
design and rationale for a randomised, controlled, multicentre clinical trial
across eight European countries.

Brouckaert J(1), Dellgren G(2), Wallinder A(3), Rega F(4).

Author information:
(1)Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium.
(2)Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
(3)XVIVO Perfusion AB, Gothenburg, Sweden.
(4)Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium
[email protected].

INTRODUCTION: Ischaemic cold static storage (ICSS) is the gold standard in donor
heart preservation. This ischaemic time frame renders a time constraint and risk
for primary graft dysfunction. Cold oxygenated heart perfusion, known as
non-ischaemic heart preservation (NIHP), theoretically limits the ischaemic
time, while holding on to the known advantage of hypothermia and cardioplegia, a
low metabolic rate.
METHODS AND ANALYSIS: The NIHP 2019 study is an international, randomised,
controlled, open, multicentre clinical trial in 15 heart transplantation centres
in 8 European countries and includes 202 patients undergoing heart
transplantation, allocated 1:1 to NIHP or ICSS. Enrolment is estimated to be 30
months after study initiation. The patients are followed for 12 months after
transplantation.The primary objective is to evaluate the effect of NIHP on
survival, allograft function and rejection episodes within the first 30 days
after transplantation. The secondary objectives are to compare treatment groups
with respect to survival, allograft function, cardiac biomarkers, rejection
episodes, allograft vasculopathy, adverse events and adverse device effects
within 12 months.
ETHICS AND DISSEMINATION: This protocol was approved by the Ethics Committee
(EC) for Research UZ/KU Leuven, Belgium, the coordinating EC in Germany (Bei Der
LMU München), the coordinating EC in the UK (West Midlands-South Birmingham
Research), the EC of Hospital Puerta de Hierro, Madrid, Spain, the EC of
Göteborg, Sweden, the coordinating EC in France, the EC of Padova, Italy and the
EC of the University of Vienna, Austria. This study will be conducted in
accordance with current local regulations and international applicable
regulatory requirements according to the principles of the Declaration of
Helsinki and ISO14155:2020. Main primary and secondary outcomes will be
published on modified intention-to-treat population and per-protocol population.
TRIAL REGISTRATION NUMBER: NCT03991923.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No

commercial re-use. See rights and permissions. Published by BMJ.

DOI: 10.1136/bmjopen-2023-073729
PMCID: PMC10759137
PMID: 38154894 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: AW is employed by the

Sponsor.

5. JAMA Cardiol. 2023 Jan 1;8(1):56-65. doi: 10.1001/jamacardio.2022.4210.

Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly
Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER
Randomized Clinical Trial.
Mc Causland FR(1)(2), Claggett BL(2)(3), Vaduganathan M(2)(3), Desai AS(2)(3),
Jhund P(4), de Boer RA(5), Docherty K(4), Fang J(6), Hernandez AF(7), Inzucchi
SE(8), Kosiborod MN(9), Lam CSP(10), Martinez F(11), Saraiva JFK(12), McGrath
MM(1)(2), Shah SJ(13), Verma S(14), Langkilde AM(15), Petersson M(15), McMurray
JJV(4), Solomon SD(2)(3).

Author information:
(1)Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston,
Massachusetts.
(2)Harvard Medical School, Boston, Massachusetts.
(3)Cardiovascular Division, Department of Medicine, Brigham and Women's
Hospital, Boston, Massachusetts.
(4)British Heart Foundation Glasgow Cardiovascular Research Centre, School of
Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, Scotland,
United Kingdom.
(5)Department of Cardiology, Erasmus Medical Center, Rotterdam, Netherlands.
(6)University of Utah School of Medicine, Salt Lake City.
(7)Duke University Medical Center, Durham, North Carolina.
(8)Yale School of Medicine, New Haven, Connecticut.
(9)Saint Luke's Mid America Heart Institute, University of Missouri, Kansas
City.
(10)National Heart Center Singapore and Duke-National University of Singapore,
Singapore.
(11)National University of Cordoba, Cordoba, Argentina.
(12)Cardiovascular Division, Instituto de Pesquisa Clínica de Campinas,
Campinas, Brazil.
(13)Northwestern University Feinberg School of Medicine, Chicago, Illinois.
(14)University of Toronto, Toronto, Ontario, Canada.
(15)Late-Stage Development, Cardiovascular, Renal and Metabolism,
BioPharmaceuticals Research and Development, AstraZeneca, Gothenburg, Sweden.

IMPORTANCE: Sodium-glucose cotransporter 2 inhibitors are known to reduce heart

failure events and slow progression of kidney disease among patients with heart
failure and a reduced ejection fraction.
OBJECTIVE: To determine the effect of dapagliflozin on cardiovascular and kidney
outcomes and the influence of baseline kidney disease among patients with heart
failure and a mildly reduced or preserved ejection fraction enrolled in the
Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved
Ejection Fraction Heart Failure (DELIVER) trial.
DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified analysis conducted
from July 1 to September 18, 2022 of the DELIVER randomized clinical trial. This
was an international, multicenter trial including patients with ejection
fraction greater than 40% and estimated glomerular filtration rate (eGFR) of 25
mL/min/1.73 m2 or higher.
INTERVENTIONS: Dapagliflozin, 10 mg, per day or placebo.
MAIN OUTCOMES AND MEASURES: Outcomes assessed were whether baseline kidney
function modified the treatment effect on the primary outcome (cardiovascular
death or worsening heart failure). Also examined was the treatment effect on the
prespecified outcomes of eGFR slope and a post hoc composite kidney outcome
(first ≥50% decline in eGFR from baseline; first eGFR <15 mL/min/1.73 m2;
end-stage kidney disease; death from kidney causes).
RESULTS: A total of 6262 patients (mean [SD] age, 72 [10] years; 3516 male
[56%]) had mean (SD) eGFR measurements available: 61 (19) mL/min/1.73 m2; 3070
patients (49%) had an eGFR less than 60 mL/min/1.73 m2. The effect of
dapagliflozin on the primary outcome was not influenced by baseline eGFR
category (eGFR ≥60 mL/min/1.73 m2: hazard ratio [HR], 0.84; 95% CI, 0.70-1.00;
eGFR 45-<60 mL/min/1.73 m2: HR, 0.68; 95% CI, 0.54-0.87; eGFR <45 mL/min/1.73
m2: HR, 0.93; 95% CI, 0.76-1.14; P for interaction = .16). Over a median (IQR)
follow-up of 2.3 (1.7-2.8) years, the overall incidence rate of the kidney
composite outcome was low (1.1 events per 100 patient-years) and was not
affected by treatment with dapagliflozin (HR, 1.08; 95% CI, 0.79-1.49). However,
dapagliflozin attenuated the decline in eGFR from baseline (difference, 0.5; 95%
CI, 0.1-0.9 mL/min/1.73 m2 per year; P = .01) and from month 1 to 36
(difference, 1.4; 95% CI, 1.0-1.8) mL/min/1.73 m2 per year; P < .001).
CONCLUSIONS AND RELEVANCE: Results of this prespecified analysis showed that
baseline kidney function did not modify the benefit of dapagliflozin in patients
with heart failure and a mildly reduced or preserved ejection fraction.
Dapagliflozin did not significantly reduce the frequency of the kidney composite
outcome, although the overall event rate was low. However, dapagliflozin slowed
the rate of decline in eGFR compared with placebo.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03619213.

DOI: 10.1001/jamacardio.2022.4210
PMCID: PMC9634592
PMID: 36326604 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of Interest Disclosures: Dr Mc Causland

reported receiving consulting fees from GlaxoSmithKline, Advanced Instruments,
and Zydus Therapeutics and grants from Fifth Eye, the National Institute of
Diabetes and Digestive and Kidney Diseases, Satellite Healthcare, and Advanced
Medical outside the submitted work. Dr Claggett reported receiving consulting
fees from Amgen, Cardurion, Corvia, and Novartis outside the submitted work. Dr
Vaduganathan reported receiving personal fees from Amgen, AstraZeneca, Baxter
HealthCare, Bayer AG, Boehringer Ingelheim, Cytokinetics, Relypsa, American
Regent, Novartis, Roche Diagnostics, Lexicon Pharmaceuticals, Galmed, Occlutech,
Impulse Dynamics, and Tricog Health outside the submitted work. Dr Desai
reported receiving grants from AstraZeneca, Abbott, Alnylam, Bayer, and
Novartis, to Brigham and Women’s Hospital; consulting fees from AstraZeneca; and
consulting fees from Abbott, Alnylam, Avidity Biopharma, Axon Therapeutics,
Bayer, Biofourmis, Boston Scientific, Cytokinetics, GlaxoSmithKline, Medpace,
Merck, Novartis, New Amsterdam Pharma, Parexel, Regeneron, Roche, and Verily
outside the submitted work. Dr Jhund reported receiving grants and
speaker/advisory fees from AstraZeneca during the conduct of the study;
speaker/advisory fees from Novartis; grants and personal fees from Boehringer
Ingelheim; clinical trial work from Bayer and NovoNordisk; grants from Analog
Devices Inc; personal fees from ProAdwise, Alkem Metablomics, and Sun
Pharmaceuticals outside the submitted work; and serving as director of Global
Clinical Trial Partners. Dr Docherty reported institutional fees paid to
University of Glasgow from AstraZeneca for work related to the DAPA-HF and
DELIVER trials; receiving speakers fees from AstraZeneca; grants from
AstraZeneca and Boehringer Ingelheim; and consulting fees from Us2.ai outside
the submitted work. Dr Fang reported being a part of the steering committee of
AstraZeneca and Amgen and the executive committee of Novartis and Abbott; being
a member of the data safety monitoring board of Boerhinger Ingelheim/Lilly and
Windtree; being on the board of directors of the Heart Failure Society of
America; and receiving grants from the American Heart Association and the
National Institutes of Health. Dr Hernandez reported receiving personal fees
from AstraZeneca, Bayer, Merck, Boston Scientific, Cytokinetics, and Bristol
Myers Squibb and grants from American Regent, Amgen, Boehringer Ingelheim,
Verily, and Somologic outside the submitted work. Dr Inzucchi reported
nonfinancial support from AstraZeneca as an executive committee member and
through travel fees to meetings during the conduct of the study; nonfinancial
support from AstraZeneca through consultant/speaker fees; nonfinancial support
from Boehringer Ingelheim through consultant/speaker/travel fees; and consultant
fees from Novo Nordisk, Merck/Pfizer, Lexicon, VTV Therapeutics, Abbott/Alere,
Esperion, and Bayer outside the submitted work. Dr Kosiborod reported receiving
personal fees (paid to institution) from Alnylam, Amgen, Applied Therapeutics,
AstraZeneca, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion
Therapeutics, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo
Nordisk, Pharmacosmos, Sanofi, Vifor Pharma; and grants from AstraZeneca and
Boehringer Ingelheim outside the submitted work. Dr Lam reported receiving
personal fees from AstraZeneca as an executive committee member of DELIVER
during the conduct of the study; grants from Bayer and Roche Diagnostics;
personal fees from Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio
AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston
Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics,
Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC,
Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc,
Radcliffe Group Ltd, ReCor Medical, Roche Diagnostics, Sanofi, Siemens
Healthcare Diagnostics; serving as consultant or on the advisory board/steering
committee/executive committee for Us2.ai; being a cofounder and nonexecutive
director of Us2.ai; and having a patent for diagnosis and prognosis of chronic
heart failure and a patent for automated clinical workflow that recognizes and
analyses 2-dimensional and Doppler echo images for cardiac measurements and the
diagnosis, prediction and prognosis of heart disease. Dr Martinez reported
receiving personal fees from AstraZeneca Modest during the conduct of the study.
Dr Saraiva reported receiving personal fees from AstraZeneca outside the
submitted work and advisory board fees from Boehringer Ingelheim, AstraZeneca,
Novo Nordisk, Lilly, Bayer, Janssen, Pfizer, and Novartis. Dr Shah reported
receiving personal fees from AstraZeneca during the conduct of the study. Dr
Verma reported receiving grants from AstraZeneca and Boehringer Ingelheim and
personal fees from Boehringer Ingelheim, Janssen, and AstraZeneca outside the
submitted work. Dr Langkilde reported being a full-time employee of and a
shareholder in AstraZeneca during the conduct of the study. Dr Petersson
reported receiving personal fees from AstraZeneca, being a paid employee of
AstraZeneca, and being a minor shareholder of AstraZeneca outside the submitted
work. Dr McMurray reported fees paid to Glasgow University from AstraZeneca for
time spent as principal investigator of DAPA-HF and co–principal investigator of
DELIVER (trials using dapagliflozin) in heart failure and meetings related to
trial; being executive committee member for DETERMINE and PRIORITIZE trials;
being an advisory board member for the AZD9977 trial; receiving
travel/accommodation fees from AstraZeneca; reported fees paid to Glasgow
University from Bayer for time spent as steering committee member for the
FINEARTS-HF trial; reported fees paid to Glasgow University from Amgen for time
spent as steering committee member for GALACTIC-HF trial and meetings related to
this trial; travel/accommodation fees from Amgen; reported fees paid to Glasgow
University from Cytokinetics for time spent as steering committee member for the
ATOMIC-HF, COSMIC-HF, and GALACTIC-HF trials and meetings and other activities
related to these trials; travel/accommodation fees from Cytokinetics; reported
fees paid to Glasgow University from Servier for time spent as steering
committee member for the GALACTIC-HF trial; reported fees paid to Glasgow
University from Theracos for time spent as principal investigator for the BEST
trial and meetings related to this trial; travel/accommodation fees from
Theracos; reported fees paid to Glasgow University from Dalcor for time spent as
steering committee member for the Dal-GenE trial and meetings related to this
trial; reported fees paid to Glasgow University from Pfizer for time spent as
steering committee member for the ARRAY-797-301 and meetings related to this
trial; reported fees paid to Glasgow University from GlaxoSmithKline (GSK) for
time spent as co–principal investigator and steering committee member,
respectively, for the Harmony-Outcomes trial (albiglutide) and 2 trials,
ASCEND-D and ASCEND-ND, using daprodustat, and meetings related to these trials;
travel/accommodation fees from GSK; reported fees paid to Glasgow University
from Bristol Myers Squibb (BMS) for time spent as a steering committee member
for the STAND-UP clinical trial (using an HNO donor) in heart failure and
meetings related to this trial; reported fees paid to Glasgow University from
Novartis for time spent executive committee member and then co–principal
investigator of ATMOSPHERE, co–principal investigator of the PARADIGM-HF trial,
and executive/steering committee member for PARACHUTE-HF, PARADISE-MI, and
PERSPECTIVE trials (with sacubitril/valsartan) and meetings/presentations
related to these trials and aliskiren and sacubitril/valsartan and for
participation in a company advisory board that meets twice per year and covers
the cardiometabolic field; personal fees from Abbott, Alkem Metabolics, Eris
Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise
Communications, Radcliffe Cardiology, Servier, and the Corpus Personal Lecture
Fees; reported fees paid to Glasgow University from Ionis Pharmaceuticals for
time spent as consultant in services related to Ionis angiotensinogen program;
travel/accommodation fees from Ionis; reported fees paid to Glasgow University
from Cardurion for participation in a company advisory board about development
of a PDE-9 inhibitor in heart failure; and receiving fees paid to Glasgow
University from Boehringer Ingelheim for participation as a consultant for Empa
Pragmatic Trial outside the submitted work. Dr Solomon reported receiving grants
from AstraZeneca, Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer,
BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast,
MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi
Pasteur, Theracos, Us2.ai for grants to institutions and personal fees from
Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer,
Boehringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics,
Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum
Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur,
Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon,
Anacardio, Akros, and Puretech Health for consulting outside the submitted work.
No other disclosures were reported.

6. Nat Commun. 2020 Jun 12;11(1):2976. doi: 10.1038/s41467-020-16782-9.

A nonrandomized open-label phase 2 trial of nonischemic heart preservation for

human heart transplantation.

Nilsson J(1), Jernryd V(2), Qin G(2), Paskevicius A(2), Metzsch C(2), Sjöberg
T(2), Steen S(2).

Author information:
(1)Department of Clinical Sciences Lund, Cardiothoracic Surgery, Lund University
and Skane University Hospital, Lund, Sweden. [email protected].
(2)Department of Clinical Sciences Lund, Cardiothoracic Surgery, Lund University
and Skane University Hospital, Lund, Sweden.

Pre-clinical heart transplantation studies have shown that ex vivo non-ischemic

heart preservation (NIHP) can be safely used for 24 h. Here we perform a
prospective, open-label, non-randomized phase II study comparing NIHP to static
cold preservation (SCS), the current standard for adult heart transplantation.
All adult recipients on waiting lists for heart transplantation were included in
the study, unless they met any exclusion criteria. The same standard acceptance
criteria for donor hearts were used in both study arms. NIHP was scheduled in
advance based on availability of device and trained team members. The primary
endpoint was a composite of survival free of severe primary graft dysfunction,
free of ECMO use within 7 days, and free of acute cellular rejection ≥2R within
180 days. Secondary endpoints were I/R-tissue injury, immediate graft function,
and adverse events. Of the 31 eligible patients, six were assigned to NIHP and
25 to SCS. The median preservation time was 223 min (IQR, 202-263) for NIHP and
194 min (IQR, 164-223) for SCS. Over the first six months, all of the patients
assigned to NIHP achieved event-free survival, compared with 18 of those
assigned to SCS (Kaplan-Meier estimate of event free survival 72.0% [95% CI
50.0-86.0%]). CK-MB assessed 6 ± 2 h after ending perfusion was 76 (IQR, 50-101)
ng/mL for NIHP compared with 138 (IQR, 72-198) ng/mL for SCS. Four deaths within
six months after transplantation and three cardiac-related adverse events were
reported in the SCS group compared with no deaths or cardiac-related adverse
events in the NIHP group. This first-in-human study shows the feasibility and
safety of NIHP for clinical use in heart transplantation. ClinicalTrial.gov,
number NCT03150147.

DOI: 10.1038/s41467-020-16782-9
PMCID: PMC7293246
PMID: 32532991 [Indexed for MEDLINE]

Conflict of interest statement: The device was patented by S.S. The patent is
now owned by XVIVO Perfusion AB (Göteborg, Sweden). XVIVO Perfusion AB had no
involvement in the study. The authors of this manuscript have no other competing
interest to disclose.

7. Circulation. 2024 Jul 23;150(4):272-282. doi: 10.1161/CIRCULATIONAHA.124.068774.

Epub 2024 Jun 6.

Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart

Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

Dewan P(#)(1), Shen L(#)(1)(2), Pedro Ferreira J(#)(3)(4), Jhund PS(1), Anand
IS(5), Chandra A(6), Chiang LM(7), Claggett B(8), Desai AS(8), Gong J(7), Lam
CSP(9), Lefkowitz MP(7), Maggioni AP(10), Martinez F(11), Packer M(12), Redfield
MM(13), Rouleau JL(14), van Veldhuisen DJ(15), Zannad F(3), Zile MR(16)(17),
Solomon SD(8), McMurray JJV(1).

Author information:
(1)BHF Cardiovascular Research Centre, University of Glasgow, UK (P.D., L.S.,
P.S.J., J.J.V.M.).
(2)School of Clinical Medicine, Hangzhou Normal University, China (L.S.).
(3)Centre d'Investigations Cliniques Plurithématique 1433 and Inserm U1116, CHRU
Nancy, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), France
(J.P.F., F.Z.).
(4)Cardiovascular Research and Development Center, Department of Surgery and
Physiology, Faculty of Medicine of the University of Porto, Portugal (J.P.F.).
(5)VA Medical Center, University of Minnesota, Minneapolis (I.S.A.).
(6)Department of Internal Medicine, University of Texas Southwestern Medical
Center, Dallas (A.C.).
(7)Novartis Pharmaceuticals, East Hanover, NJ (L.-M.C., J.G., M.P.L.).
(8)Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA (B.C.,
A.S.D., S.D.S.).
(9)National Heart Centre Singapore and Duke-National University of Singapore
(C.S.P.L.).
(10)National Association of Hospital Cardiologists Research Centre, Florence,
Italy (A.P.M.).
(11)National University of Cordoba, Argentina (F.M.).
(12)Baylor Heart and Vascular Institute, Baylor University Medical Centre,
Dallas, TX (M.P.).
(13)Mayo Clinic, Rochester, MN (M.M.R.).
(14)Institut de Cardiologie de Montreal, Universite de Montreal, Quebec, Canada
(J.L.R.).
(15)Department of Cardiology, University Medical Centre Groningen, University of
Groningen, the Netherlands (D.J.v.V.).
(16)Medical University of South Carolina, Charleston (M.R.Z.).
(17)Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston,
SC (M.R.Z.).
(#)Contributed equally

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan

might cause cognitive impairment because neprilysin is one of several enzymes
degrading amyloid-β peptides in the brain, some of which are neurotoxic and
linked to Alzheimer-type dementia. To address this, we examined the effect of
sacubitril/valsartan compared with valsartan on cognitive function in patients
with heart failure with preserved ejection fraction in a prespecified substudy
of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin
Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure
With Preserved Ejection Fraction).
METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in
a subset of patients with the Mini-Mental State Examination (MMSE; score range,
0-30, with lower scores reflecting worse cognitive function). The prespecified
primary analysis of this substudy was the change from baseline in MMSE score at
96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score
of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of
dementia-related adverse events.
RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE
score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to
valsartan. Their mean age was 73 years, and the median follow-up was 32 months.
The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan
group, with 10% having an MMSE score <24; the corresponding numbers were nearly
identical in the valsartan group. The mean change from baseline to 96 weeks in
the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in
the valsartan group was -0.04 (0.07). The mean between-treatment difference at
week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point
decline in MMSE, decrease to a score <24, dementia-related adverse events, and
combinations of these showed no difference between sacubitril/valsartan and
valsartan. No difference was found in the subgroup of patients tested for
apolipoprotein E ε4 allele genotype.
CONCLUSIONS: Patients with heart failure with preserved ejection fraction in
PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured
by MMSE, did not differ between treatment with sacubitril/valsartan and
treatment with valsartan in patients with heart failure with preserved ejection
fraction.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier:
NCT01920711.

DOI: 10.1161/CIRCULATIONAHA.124.068774
PMID: 38841854 [Indexed for MEDLINE]

Conflict of interest statement: Dr Jhund reports receiving grant support from

Boehringer Ingelheim and fees for serving on an advisory board from
Cytokinetics. Dr Anand reports receiving fees for serving on a steering
committee from AstraZeneca, ARCA biopharma, Amgen, and LivaNova; fees for
serving as chair of a data and safety monitoring board from Boston Scientific;
fees for serving on an end-point committee from Boehringer Ingelheim; and fees
for serving on an advisory board from Zensun. Dr Claggett received consulting
fees from AOBiome, Biogen, Boehringer Ingelheim, Corvia Medical, Gilead
Sciences, and MyoKardia. Dr Desai received consulting fees from Abbott,
Boehringer Ingelheim, DalCor Pharmaceuticals, and Regeneron; grant support, paid
to Brigham and Women’s Hospital, consulting fees, and fees for serving on an
advisory board from Alnylam Pharmaceuticals and AstraZeneca; consulting fees and
fees for serving on a steering committee from Biofourmis; consulting fees and
fees for serving on a data and safety monitoring committee from Boston
Scientific; fees for serving on an advisory board from Corvidia; and fees for
serving on an advisory board and consulting fees from Relypsa. Drs Chiang, Gong,
and Lefkowitz are employed by Novartis Pharmaceuticals. Dr Lam received grant
support and fees for serving on an advisory board from Boston Scientific and
Roche Diagnostics; grant support, fees for serving on an advisory board, and
fees for serving on steering committees from Bayer; grant support from
Medtronics; grant support and fees for serving on a steering committee from
Vifor Pharma; fees for serving on an advisory board and fees for serving on
steering committees from AstraZeneca and Novartis; fees for serving on an
advisory board from Amgen, Boehringer Ingelheim, and Abbott Diagnostics;
consulting fees from Merck and Stealth BioTherapeutics; fees for serving on a
steering committee from Janssen Research and Development; lecture fees and
consulting fees from Menarini; and fees for serving on a scientific committee
from Corvia Medical and holding a pending patent (PCT/SG2016/050217) on a method
regarding diagnosis and prognosis of chronic heart failure. Dr Maggioni received
fees for serving on a study committee from Bayer and Fresenius. Dr Packer
received consulting fees from AbbVie, Akcea Therapeutics, Actavis, Amgen,
AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead
Sciences, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic
Biologics, and Theravance Biopharma. Dr Rouleau received consulting fees from
AstraZeneca. Dr van Veldhuisen received fees for serving on a steering committee
and travel support from ARCA Biopharma and Corvia Medical. Dr Zannad received
fees for serving on a steering committee from Janssen, Bayer, Boston Scientific,
CVRx, and Boehringer Ingelheim; consulting fees from Amgen, Vifor
Pharma–Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, and
Merck; and consulting fees and fees for serving on a steering committee from
AstraZeneca and serving as founder of cardiorenal and CVCT. Dr Zile received
fees for serving on a steering committee from Abbott and Ironwood Pharma;
consulting fees from Boston Scientific and MyoKardia; grant support and fees for
serving on a steering committee from CVRx and Medtronic; fees for serving on an
eligibility committee from EBR Systems and V-Wave; fees for serving on a
clinical-events committee from Endotronics; and fees for serving on a data and
safety monitoring board from Merck. Dr Solomon received grant support, paid to
Brigham and Women’s Hospital, and consulting fees from Alnylam Pharmaceuticals,
Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline,
MyoKardia, Novartis, Theracos, Bayer, and Cytokinetics; grant support, paid to
Brigham and Women’s Hospital, from Bellerophon Therapeutics, Celladon, Ionis
Pharmaceuticals, Lonestar Heart, Mesoblast, Sanofi Pasteur, and Eidos
Therapeutics; consulting fees from Akros Pharma, Corvia Medical, Ironwood
Pharma, Merck, Roche, Takeda Pharmaceutical, Quantum Genomics, AOBiome, Cardiac
Dimensions, Tenaya Therapeutics, and Daiichi Sankyo; and fees for serving on a
data and safety monitoring board from Janssen. Dr McMurray reports that his
employer, Glasgow University, has been paid by Novartis for serving as an
executive committee member and coprincipal investigator of ATMOSPHERE,
PARADIGM-HF, and PARAGON-HF trials and executive/steering committee member of
the PARADISE-MI and PERSPECTIVE trials (with sacubitril/valsartan) and for
meetings/presentations related to these trials, aliskiren, and
sacubitril-valsartan. Novartis has also paid for his travel and accommodation
for some of these meetings. Glasgow University has also been paid by Novartis
for advisory board; by Bayer for serving as a steering committee member of the
PANACHE trial using neladenoson bialanate (BAY 1067197); by Cardiorentis for
serving as a steering committee member and end-point committee chair for the
TRUE-AHF trial and attending meetings related to this trial; by Cardiorentis for
travel and accommodation to attend some of these meetings; by Amgen for serving
as steering committee member for the ATOMIC-HF and COSMIC-HF trials and
attending meetings related to this trial; by Amgen for travel and accommodation
for some of these meetings; by Oxford University (which received a grant from
Bayer, which manufactures acarbose) for serving as a steering committee member
for the ACE trial (using acarbose) and attending meetings related to this trial;
by Theracos for serving as principal investigator for the BEST trial and
attending meetings related to this trial; by Theracos for travel and
accommodation to attend some of these meetings; by Abbvie (which manufactures
atrasentan) for serving as steering committee member for the SONAR trial (using
atrasentan) and to attend meetings related to this trial; by Abbvie for his
travel and accommodation to attend some of these meetings; by DalCor
Pharmaceuticals for serving as steering committee member for the Dal-GenE trial
and to attend meetings related to this trial; by Pfizer for serving on the data
safety monitoring committee for the SPIRE trial and to attend meetings related
to this trial; by Merck for serving on the data safety monitoring committee for
the MK-3102 program, for the VICTORIA trial, and to attend meetings related to
these trials; by AstraZeneca (which markets dapagliflozin) for serving as
principal investigator of DAPA-HF and coprincipal investigator of DELIVER
(trials using dapagliflozin on heart failure) and to attend meetings related
trial; by AstraZeneca for his travel and accommodation to attend meetings; by
GSK for serving as coprincipal investigator and steering committee member for
the Harmony-Outcomes trial (albiglutide) and the trials ASCEND-D and ASCEND-ND,
using daprodustat, respectively, and to attend meetings related to these trials;
by GSK for his travel and accommodation to attend some of the meetings; by BMS
for serving as a steering committee member for the STAND-UP clinical trial
(using an HNO donor) on heart failure and to attend meetings related to this
trial; and by Kings College Hospital (which has received a grant from KRUK and
Vifor-Fresenius, which manufactures intravenous iron) for serving as steering
committee member for the PIVOTAL trial (using intravenous iron) and for running
the end-point adjudication committee for this trial, to attend meetings related
to PIVOTAL, and for his travel and accommodation for to attend some of the
meetings. All payments were made through consultancies with Glasgow University,
and Dr McMurray has not received any personal payments in relation to the trials
or drugs. The other authors report no conflicts. The study supporters had no
role in the design and conduct of the study; collection, management, analysis,
and interpretation of the data; preparation, review, or approval of the
manuscript; or decision to submit the manuscript for publication.

8. Lancet. 2015 Jun 27;385(9987):2577-84. doi: 10.1016/S0140-6736(15)60261-6. Epub

2015 Apr 14.

Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II):
a prospective, open-label, multicentre, randomised non-inferiority trial.

Ardehali A(1), Esmailian F(2), Deng M(3), Soltesz E(4), Hsich E(4), Naka Y(5),
Mancini D(5), Camacho M(6), Zucker M(6), Leprince P(7), Padera R(8), Kobashigawa
J(2); PROCEED II trial investigators.

Collaborators: Baran D, Livi U, Guzzi G, Tsui S, Simon A, Madsen J.

Author information:
(1)UCLA Medical Center, Los Angeles, CA, USA. Electronic address:
[email protected].
(2)The Cedars-Sinai Heart Institute, Los Angeles, CA, USA.
(3)UCLA Medical Center, Los Angeles, CA, USA.
(4)Cleveland Clinic Foundation, Cleveland, OH, USA.
(5)Columbia University Medical Center, New York, NY, USA.
(6)St Barnabas Heart Center, Newark Beth Israel Medical Center, Newark, NJ, USA.
(7)Hôpital de la Pitié-Salpêtrière, Paris, France.
(8)Brigham and Women's Hospital, Boston, MA, USA.

Comment in
Lancet. 2015 Jun 27;385(9987):2552-4. doi: 10.1016/S0140-6736(15)60614-6.

BACKGROUND: The Organ Care System is the only clinical platform for ex-vivo
perfusion of human donor hearts. The system preserves the donor heart in a warm
beating state during transport from the donor hospital to the recipient
hospital. We aimed to assess the clinical outcomes of the Organ Care System
compared with standard cold storage of human donor hearts for transplantation.
METHODS: We did this prospective, open-label, multicentre, randomised
non-inferiority trial at ten heart-transplant centres in the USA and Europe.
Eligible heart-transplant candidates (aged >18 years) were randomly assigned
(1:1) to receive donor hearts preserved with either the Organ Care System or
standard cold storage. Participants, investigators, and medical staff were not
masked to group assignment. The primary endpoint was 30 day patient and graft
survival, with a 10% non-inferiority margin. We did analyses in the
intention-to-treat, as-treated, and per-protocol populations. This trial is
registered with ClinicalTrials.gov, number NCT00855712.
FINDINGS: Between June 29, 2010, and Sept 16, 2013, we randomly assigned 130
patients to the Organ Care System group (n=67) or the standard cold storage
group (n=63). 30 day patient and graft survival rates were 94% (n=63) in the
Organ Care System group and 97% (n=61) in the standard cold storage group
(difference 2·8%, one-sided 95% upper confidence bound 8·8; p=0·45). Eight (13%)
patients in the Organ Care System group and nine (14%) patients in the standard
cold storage group had cardiac-related serious adverse events.
INTERPRETATION: Heart transplantation using donor hearts adequately preserved
with the Organ Care System or with standard cold storage yield similar
short-term clinical outcomes. The metabolic assessment capability of the Organ
Care System needs further study.
FUNDING: TransMedics.

Copyright © 2015 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S0140-6736(15)60261-6
PMID: 25888086 [Indexed for MEDLINE]

9. Pediatr Transplant. 2016 Sep;20(6):859-65. doi: 10.1111/petr.12737. Epub 2016

Jul 6.

Successful orthotopic heart transplantation using a donor heart with ALCAPA.

Simmonds JD(1), Mustafa M(1), Fajardo Jaramillo DP(1), Bellsham-Revell HR(1),

Marek J(1), Burch M(1), Tsang VT(1), Muthialu N(1).

Author information:
(1)Cardiac Services, Great Ormond Street Hospital for Children, London, UK.

Comment in
Pediatr Transplant. 2016 Sep;20(6):740-1. doi: 10.1111/petr.12772.

With the imbalance between donation rates and potential recipients growing,
transplant programs are increasingly using non-ideal organs from so-called
marginal donors. This is the first reported case of the intentional use of a
donor heart with ALCAPA. The recipient was aged one yr with restrictive
cardiomyopathy who had been supported with BiVAD for over six months. Function
of the donor left ventricle was shown to be well preserved, with no obvious
signs of ischemia, except for a fibrotic layer on the anterolateral papillary
muscle of the mitral valve. To prevent coronary steal, the anomalous left
coronary artery ostium from the MPA was oversewn prior to implantation. The
transplanted heart spontaneously regained sinus rhythm immediately following
cross-clamp release and showed good contractility from the first postoperative
echocardiogram. The patient continues to do well 18 months post-transplant, with
excellent function on echocardiography, and good flow on coronary angiography.
© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

DOI: 10.1111/petr.12737
PMID: 27384867 [Indexed for MEDLINE]

10. Int J Obstet Anesth. 2018 Aug;35:104-107. doi: 10.1016/j.ijoa.2018.04.003. Epub

2018 Apr 24.

Pregnancy after heterotopic heart transplant removal.

Churchill S(1), de Lloyd L(2), Francis HC(3), Wallis H(4).

Author information:
(1)Department of Anaesthetics, University Hospital of Wales, Cardiff, United
Kingdom. Electronic address: [email protected].
(2)Department of Anaesthetics, University Hospital of Wales, Cardiff, United
Kingdom.
(3)Department of Obstetrics, University Hospital of Wales, Cardiff, United
Kingdom.
(4)Department of Cardiology, University Hospital of Wales, Cardiff, United
Kingdom.

Heterotopic heart transplants were introduced in 1974. The technique allows the
patient's native heart to be preserved in situ, alongside the transplanted
heterotopic donor heart. We present the case of a nulliparous woman who
underwent heterotopic heart transplant in infancy, and subsequent explantation
of the donor heart eleven years later, when her native heart function recovered.
In adulthood the patient attended pre-pregnancy counselling and was awaiting
cardiac magnetic resonance imaging when she presented pregnant at
6 weeks-of-gestation. She attended the joint cardiac obstetric and anaesthetic
clinic, where she was reviewed monthly and had bi-monthly echocardiograms. At
35 weeks-of-gestation she was admitted to hospital with preeclampsia. After
blood pressure control and steroid administration, a category 3 caesarean
delivery under spinal anaesthesia was performed. To our knowledge this is the
first case report describing pregnancy in a patient with a removed heterotopic
heart transplant.

Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.ijoa.2018.04.003
PMID: 29773485 [Indexed for MEDLINE]

11. J Cardiothorac Surg. 2015 Dec 18;10:186. doi: 10.1186/s13019-015-0393-8.

Successful heart transplantation after prolonged cardiac arrest and

extracorporeal life support in organ donor-a case report.

Arroyo D(1)(2), Gasche Y(3)(4), Banfi C(5)(4)(6), Stiasny B(7), Bendjelid

K(3)(4)(6), Giraud R(3)(4)(6).

Author information:
(1)Intensive Care Unit, Geneva University Hospitals, Rue Gabrielle Perret-Gentil
4, CH-1211, Geneva, Switzerland. [email protected].
(2)Geneva Hemodynamic Research Group, Geneva, Switzerland. [email protected].
(3)Intensive Care Unit, Geneva University Hospitals, Rue Gabrielle Perret-Gentil
4, CH-1211, Geneva, Switzerland.
(4)Faculty of Medicine, University of Geneva, Geneva, Switzerland.
(5)Division of Cardiovascular Surgery, Geneva University Hospitals, Geneva,
Switzerland.
(6)Geneva Hemodynamic Research Group, Geneva, Switzerland.
(7)Divisions of Pediatric Cardiology and Children's Research Centre, University
Children's Hospital Zurich, Geneva, Switzerland.

BACKGROUND: Although heart transplantation is a successful therapy for patients

suffering from end-stage heart failure, the therapeutic is limited by the lack
of organs. Donor cardiac arrest is a classic hindrance to heart retrieval as it
raises issues on post-transplant outcomes.
CASE PRESENTATION: The present case reports a successful heart transplantation
after prolonged donor cardiac arrest (total lowflow time of 95 minutes) due to
anaphylactic shock necessitating extracorporeal life support. We further provide
an overview of the current evidence and outcomes of heart transplantation in
cases of donor cardiac arrest.
CONCLUSION: Providing that donor and recipient criteria are respected, donor
cardiac arrest does not seem to be an adverse predictor in heart
transplantation.

DOI: 10.1186/s13019-015-0393-8
PMCID: PMC4684616
PMID: 26682544 [Indexed for MEDLINE]

12. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2017 Jan;20:20-27. doi:
10.1053/j.pcsu.2016.09.009.

Mechanical Circulatory Support of the Fontan Patient.

Woods RK(1), Ghanayem NS(2), Mitchell ME(3), Kindel S(4), Niebler RA(5).

Author information:
(1)Department of Surgery, Division of Pediatric Cardiothoracic Surgery, Medical
College of Wisconsin, Milwaukee, WI; Herma Heart Center, Children's Hospital of
Wisconsin, Milwaukee, WI. Electronic address: [email protected].
(2)Department of Pediatrics, Division of Critical Care, Medical College of
Wisconsin, Milwaukee, WI.
(3)Department of Surgery, Division of Pediatric Cardiothoracic Surgery, Medical
College of Wisconsin, Milwaukee, WI; Herma Heart Center, Children's Hospital of
Wisconsin, Milwaukee, WI.
(4)Department of Pediatrics, Division of Cardiology, Medical College of
Wisconsin, Milwaukee, WI; Herma Heart Center, Children's Hospital of Wisconsin,
Milwaukee, WI.
(5)Department of Pediatrics, Division of Critical Care, Medical College of
Wisconsin, Milwaukee, WI; Herma Heart Center, Children's Hospital of Wisconsin,
Milwaukee, WI.

Because of the inadequacies inherent to a circulation supported by a single

ventricle, many Fontan patients will experience failure of their circulation. To
date, there is no medical regimen that reliably and consistently restores
circulatory function in these patients. Because of the shortage of donor organs
and the fact that many of these patients present with features that either
preclude or render heart transplantation a high risk, there is an intense need
to better understand how mechanical circulatory support (MCS) may benefit these
patients. In this report, we share our experience of successful MCS and
transplantation of three patients. Our experience and that of others is very
encouraging, but also preliminary. In general, a systemic ventricular assist
device, with or without a Fontan fenestration, is a reasonable consideration for
a patient presenting with predominantly systolic dysfunction. A
pulmonary/systemic venous assist device may be sufficient for the patient with
preserved systolic function and failure of the systemic venous/lymphatic system;
however, this remains speculative. The more comprehensive approach of a total
artificial heart or bilateral support is attractive in theory, but beset by the
need for a more complex operation. In all scenarios, early referral, before
organ failure, is paramount to successful MCS.

Copyright © 2017 Elsevier Inc. All rights reserved.

DOI: 10.1053/j.pcsu.2016.09.009
PMID: 28007060 [Indexed for MEDLINE]

13. J Heart Lung Transplant. 2017 Mar;36(3):258-263. doi:

10.1016/j.healun.2016.08.015. Epub 2016 Aug 20.

Intermediate outcomes with ex-vivo allograft perfusion for heart

transplantation.

Chan JL(1), Kobashigawa JA(2), Reich HJ(1), Ramzy D(1), Thottam MM(2), Yu Z(2),
Aintablian TL(2), Liou F(2), Patel JK(2), Kittleson MM(2), Czer LS(2), Trento
A(1), Esmailian F(3).

Author information:
(1)Cedars-Sinai Heart Institute, Los Angeles, California, USA; Department of
Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
(2)Cedars-Sinai Heart Institute, Los Angeles, California, USA.
(3)Cedars-Sinai Heart Institute, Los Angeles, California, USA; Department of
Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA. Electronic
address: [email protected].

Comment in
J Heart Lung Transplant. 2017 Mar;36(3):247-249. doi:
10.1016/j.healun.2017.01.002.

BACKGROUND: The Organ Care System, an ex-vivo heart perfusion platform,

represents an alternative to the current standard of cold organ storage that
sustains the donor heart in a near-physiologic state. It is unknown whether
using the Organ Care System influences 2-year outcomes after heart
transplantation. We reviewed our institutional experience to compare 2-year
outcomes for patients randomized to the Organ Care System or standard cold
storage.
METHODS: Between 2011 and 2013, heart transplant candidates from a single
tertiary-care medical center enrolled within the PROCEED II trial were
randomized to either standard cold storage or the Organ Care System. Outcomes
assessed included 2-year survival, freedom from cardiac allograft vasculopathy
(CAV), non-fatal major cardiac events (NF-MACE), biopsy-proven cellular
rejection (CMR) and biopsy-proven antibody-mediated rejection (AMR).
RESULTS: Thirty-eight patients were randomized to the Organ Care System (n = 19)
or cold storage group (n = 19). There was no significant difference in 2-year
patient survival (Organ Care System: 72.2%; cold storage: 81.6%; p = 0.38).
Similarly, there were no differences in freedom from CAV, NF-MACE, CMR or AMR.
The Organ Care System group had significantly longer total ischemia time (361 ±
96 minutes vs 207 ± 50 minutes; p < 0.001) and shorter cold ischemia time (134 ±
45 minutes vs 207 ± 50 minutes; p < 0.001) compared with the cold storage group.
CONCLUSION: The Organ Care System did not appear to be associated with
significant differences in intermediate results compared with conventional
strategies. These results suggest that this ex-vivo allograft perfusion system
is a promising and valid platform for donor heart transportation.
Copyright © 2017 International Society for Heart and Lung Transplantation.
Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.healun.2016.08.015
PMID: 27646064 [Indexed for MEDLINE]

14. Perfusion. 2015 Sep;30(6):499-506. doi: 10.1177/0267659114550234. Epub 2014 Sep

23.

Tissue perfusion in neonates undergoing open-heart surgery using autologous

umbilical cord blood or donor blood components.

Chasovskyi K(1), Fedevych O(2), McMullan DM(3), Mykychak Y(2), Vorobiova G(4),
Zhovnir V(5), Yemets I(2).

Author information:
(1)Perfusiology, Ukrainian Children's Cardiac Center, Kyiv, Ukraine
[email protected].
(2)Surgery, Ukrainian Children's Cardiac Center, Kyiv, Ukraine.
(3)Surgery, Seattle Children's Hospital, USA.
(4)Immunology, Ukrainian Children's Cardiac Center, Kyiv, Ukraine.
(5)Anesthesiology, Ukrainian Children's Cardiac Center, Kyiv, Ukraine.

BACKGROUND: This study evaluates the hemoglobin-oxygen relationship and tissue

perfusion during cardiopulmonary bypass (CPB) in neonates undergoing open-heart
surgery using autologous umbilical cord blood or donor blood components.
METHODS: We compared perioperative hematocrit (Hct), fetal hemoglobin (HbF),
p(50)O(2), pH, pCO(2), serum lactate, duration of mechanical ventilation and
intensive care unit (ICU) length of stay in neonates undergoing open-heart
surgery using autologous umbilical cord blood (Group I, N=45) or donor blood
components (Group II, N=65). The groups were similar with respect to diagnosis,
weight, type of procedure, duration of CPB and duration of myocardial ischemia.
RESULTS: Mean p(50)O(2) was significantly lower in Group I during CPB (19.7 vs.
22.3 mmHg, p=0.004) and at the end of CPB (20.1 vs. 22.8 mmHg, p=0.003). Median
peak lactate during CPB was higher in Group I (4.8 vs. 2.2 mmol/l, p<0.001).
Carbon dioxide tension was identified as an independent predictor of higher
p(50)O(2) during CPB in Group I (β=0.88, p=0.002), but not Group II. Bodyweight,
Hct, duration of CPB, pre-CPB lactate level and pCO(2) affected peak lactate
level during CPB. Although mean duration of ventilation was longer in Group II
(mean 51 vs. 43, p=0.004), the groups experienced similar duration of ICU stay
(5.8 vs. 5.9 days, p=0.280).
CONCLUSIONS: Despite the fact that the oxyhemoglobin dissociation curve is
shifted leftward in patients who receive autologous umbilical cord blood, tissue
oxygen delivery appears to be preserved in neonates who undergo open-heart
surgery using autologous umbilical cord blood.

© The Author(s) 2014.

DOI: 10.1177/0267659114550234
PMID: 25249520 [Indexed for MEDLINE]

15. J Heart Lung Transplant. 2017 Jul;36(7):744-753. doi:

10.1016/j.healun.2017.02.011. Epub 2017 Feb 20.

Standard donor lung procurement with normothermic ex vivo lung perfusion: A

prospective randomized clinical trial.
Slama A(1), Schillab L(2), Barta M(2), Benedek A(2), Mitterbauer A(2),
Hoetzenecker K(2), Taghavi S(2), Lang G(3), Matilla J(2), Ankersmit H(2), Hager
H(4), Roth G(4), Klepetko W(2), Aigner C(5).

Author information:
(1)Department of Thoracic Surgery, Medical University of Vienna, Vienna,
Austria; Department of Thoracic Surgery and Surgical Endoscopy,
Ruhrlandklinik-University Clinic Essen, Essen, Germany.
(2)Department of Thoracic Surgery, Medical University of Vienna, Vienna,
Austria.
(3)Department of Thoracic Surgery, Medical University of Vienna, Vienna,
Austria; Department of Thoracic Surgery, Semmelweis University, National
Institute of Oncology, Budapest, Hungary.
(4)Department of Anaesthesia, General Intensive Care and Pain Management,
Medical University of Vienna, Vienna, Austria.
(5)Department of Thoracic Surgery, Medical University of Vienna, Vienna,
Austria; Department of Thoracic Surgery and Surgical Endoscopy,
Ruhrlandklinik-University Clinic Essen, Essen, Germany. Electronic address:
[email protected].

Comment in
J Heart Lung Transplant. 2017 Jul;36(7):720-721. doi:
10.1016/j.healun.2017.03.009.

BACKGROUND: Ex vivo lung perfusion (EVLP) was primarily developed for evaluation
of impaired donor lungs. The good clinical results raise the question for its
possible impact on lungs meeting standard criteria. Before application of EVLP
on such lungs enters routine clinical practice, it must be demonstrated whether
EVLP would affect or improve outcome when used in standard donor lungs. We
performed a prospective randomized trial to investigate the role of EVLP in
standard lung transplantation (Tx).
METHODS: This prospective randomized clinical trial compared patients who
underwent Tx with ex vivo evaluated donor lungs with an equivalent patient
population without previous EVLP.
RESULTS: From October 2013 to May 2015, 193 lung Tx were performed at the
Medical University of Vienna. During this period, 80 recipient/donor pairs that
met the inclusion criteria were included in this trial, 41 pairs in the control
group, and 39 in the EVLP group. In the EVLP group, 4 lungs (10.2%) ultimately
did not qualify for Tx and were rejected for lung Tx owing to technical reasons
(n = 2) and quality criteria (n = 2). Donor and recipient characteristics were
comparable in both groups. Total cold ischemic time in the EVLP group was
significantly longer for both implanted lungs (first side, 372 minutes vs 291
minutes, p < 0.001; second side, 437 minutes vs 370 minutes, p = 0.001); median
duration of surgery showed no differences (277 minutes vs 275 minutes). Median
oxygen partial pressure/fraction of inspired oxygen ratio at 24 hours after Tx
was 516 (range, 280-557) in the EVLP group and 491 (range, 352-575) in the
control group (p = 0.63). Incidence of primary graft dysfunction >1 was lower in
the EVLP group at all time points compared with the control group (24 hours,
5.7% vs 19.5%, p = 0.10), and need for post-operative prolonged extracorporeal
membrane oxygenation was lower in the EVLP group (5.7% vs 12.2%, p = 0.44).
Short-term clinical outcomes did not differ between recipients in the 2 groups.
Patients remained intubated (1.6 days vs 1.6 days, p = 0.67), in the intensive
care unit (6 days vs 6 days, p = 0.76), and in the hospital (23 days vs 19 days,
p = 0.42) for a comparable period of time. The 30-day survival was 97.1% vs 100%
(p = 0.46).
CONCLUSIONS: This study provides evidence that EVLP can safely be used in
standard donor lungs. Functional results and perioperative outcome are
comparable to those achieved with standard donor lung preservation techniques.
As an evaluation tool, EVLP allows clinicians to identify and to possibly
exclude lungs with functional impairment. Finally, EVLP can safely extend total
preservation time.

Copyright © 2017 International Society for the Heart and Lung Transplantation.
Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.healun.2017.02.011
PMID: 28314503 [Indexed for MEDLINE]

16. Intern Med J. 2017 Oct;47(10):1202-1205. doi: 10.1111/imj.13568.

Long distance heart transplantation: a tale of two cities.

Jain P(1), Prichard RA(1)(2), Connellan MB(1)(3), Dhital KK(1)(3)(4), Macdonald

PS(1)(3)(4).

Author information:
(1)Heart Transplant Unit, St Vincent's Hospital, Sydney, New South Wales,
Australia.
(2)University of Technology, Sydney, New South Wales, Australia.
(3)Department of Medicine, University of New South Wales, Sydney, New South
Wales, Australia.
(4)Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.

In this 'paired' case report, we describe two heart transplants performed 3 days
apart at our centre. Both cases involved very prolonged transportation time of
the donor heart. In one case, the donor heart was transported in an ice chest,
while in the other case the organ was transported using a normothermic ex vivo
perfusion (NEVP) system. The additional retrieval costs incurred by the use NEVP
were more than offset by the reduction in subsequent inpatient costs.

© 2017 Royal Australasian College of Physicians.

DOI: 10.1111/imj.13568
PMID: 28994259 [Indexed for MEDLINE]

17. J Card Surg. 2021 Jul;36(7):2592-2595. doi: 10.1111/jocs.15519. Epub 2021 Mar
30.

Successful heart transplantation after 17 h ex vivo time using the Organ Care
System-3 years follow-up.

Medressova A(1), Faizov L(1), Kuanyshbek A(1), Kaliyev R(1), Myrzakhmetova G(1),
la Fleur P(2), Pya Y(1).

Author information:
(1)National Research Cardiac Surgery Center, Nur-Sultan, Kazakhstan.
(2)Nazarbayev University School of Medicine, Nur-Sultan, Kazakhstan.

Cold storage preservation is the standard approach for heart transplantation but
is a time-limited method of care. Ex vivo heart perfusion expands the donor pool
due by mitigating time and distance barriers and allows the possibility to
improve graft function. We report long term follow up of a successful heart
transplantation following an ex vivo time of 17 h using the Organ Care System in
a patient with a left ventricular assist device.
© 2021 Wiley Periodicals LLC.

DOI: 10.1111/jocs.15519
PMID: 33783046 [Indexed for MEDLINE]

18. J Clin Invest. 2020 May 1;130(5):2270-2285. doi: 10.1172/JCI133530.

Donor glucose-6-phosphate dehydrogenase deficiency decreases blood quality for

transfusion.

Francis RO(1), D'Alessandro A(2), Eisenberger A(3), Soffing M(4), Yeh R(4),
Coronel E(4), Sheikh A(5), Rapido F(6), La Carpia F(1), Reisz JA(2), Gehrke
S(2), Nemkov T(2), Thomas T(1), Schwartz J(1), Divgi C(4), Kessler D(7), Shaz
BH(7), Ginzburg Y(8), Zimring JC(9), Spitalnik SL(1), Hod EA(1).

Author information:
(1)Department of Pathology and Cell Biology, Columbia University Vagelos College
of Physicians and Surgeons and NewYork-Presbyterian Hospital, New York, New
York, USA.
(2)University of Colorado Denver-Anschutz Medical Campus, Aurora, Colorado, USA.
(3)Department of Medicine and.
(4)Department of Nuclear Medicine, Columbia University Vagelos College of
Physicians and Surgeons and NewYork-Presbyterian Hospital, New York, New York,
USA.
(5)Division of Nuclear Medicine and Molecular Imaging, Icahn School of Medicine
at Mount Sinai Hospital, New York, New York, USA.
(6)Department of Anesthesia and Critical Care Medicine, Montpellier University
Hospital Gui de Chauliac, Montpellier, France.
(7)New York Blood Center, New York, New York, USA.
(8)Division of Hematology Oncology, Icahn School of Medicine at Mount Sinai
Hospital, New York, New York, USA.
(9)Carter Immunology Center, University of Virginia School of Medicine,
Charlottesville, Virginia, USA.

BACKGROUNDGlucose-6-phosphate dehydrogenase (G6PD) deficiency decreases the

ability of red blood cells (RBCs) to withstand oxidative stress. Refrigerated
storage of RBCs induces oxidative stress. We hypothesized that G6PD-deficient
donor RBCs would have inferior storage quality for transfusion as compared with
G6PD-normal RBCs.METHODSMale volunteers were screened for G6PD deficiency; 27
control and 10 G6PD-deficient volunteers each donated 1 RBC unit. After 42 days
of refrigerated storage, autologous 51-chromium 24-hour posttransfusion RBC
recovery (PTR) studies were performed. Metabolomics analyses of these RBC units
were also performed.RESULTSThe mean 24-hour PTR for G6PD-deficient subjects was
78.5% ± 8.4% (mean ± SD), which was significantly lower than that for
G6PD-normal RBCs (85.3% ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers
(0/27) and 3 G6PD-deficient volunteers (3/10) had PTR results below 75%, a key
FDA acceptability criterion for stored donor RBCs. As expected, fresh
G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose
phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated
increased glycolysis, impaired glutathione homeostasis, and increased purine
oxidation, as compared with G6PD-normal RBCs. In addition, there were
significant correlations between PTR and specific metabolites in these
pathways.CONCLUSIONBased on current FDA criteria, RBCs from G6PD-deficient
donors would not meet the requirements for storage quality. Metabolomics
assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate
ratios), along with potential compensatory pathways that could be leveraged to
ameliorate the metabolic needs of G6PD-deficient RBCs.TRIAL
REGISTRATIONClinicalTrials.gov NCT04081272.FUNDINGThe Harold Amos Medical
Faculty Development Program, Robert Wood Johnson Foundation grant 71590, the
National Blood Foundation, NIH grant UL1 TR000040, the Webb-Waring Early Career
Award 2017 by the Boettcher Foundation, and National Heart, Lung, and Blood
Institute grants R01HL14644 and R01HL148151.

DOI: 10.1172/JCI133530
PMCID: PMC7191001
PMID: 31961822 [Indexed for MEDLINE]

Conflict of interest statement: Conflict of interest: AD and TN are founders of

Omix Technologies, Inc. and Altis Biosciences, LLC. SLS is a consultant for
Tioma, Inc. AD and SLS are members of the Scientific Advisory Board of Hemanext,
Inc.

19. N Engl J Med. 2021 Jan 7;384(1):11-19. doi: 10.1056/NEJMoa2027372.

Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host

Disease.

Farag SS(1), Abu Zaid M(1), Schwartz JE(1), Thakrar TC(1), Blakley AJ(1),
Abonour R(1), Robertson MJ(1), Broxmeyer HE(1), Zhang S(1).

Author information:
(1)From the Indiana University School of Medicine (S.S.F., M.A.Z., J.E.S., R.A.,
M.J.R., H.E.B., S.Z.), Indiana University Health (S.S.F., M.A.Z., J.E.S.,
T.C.T., R.A., M.J.R.), and Indiana University Simon Comprehensive Cancer Center
(S.S.F., A.J.B., H.E.B.) - all in Indianapolis.

Comment in
N Engl J Med. 2021 Apr 8;384(14):1374-1375. doi: 10.1056/NEJMc2101975.
N Engl J Med. 2021 Apr 8;384(14):1375. doi: 10.1056/NEJMc2101975.

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane

receptor expressed on T cells, has a costimulatory function in activating T
cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host
disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of
DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell
transplantation is not known.
METHODS: We conducted a two-stage, phase 2 clinical trial to test whether
sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II
to IV acute GVHD from 30% to no more than 15% by day 100. Patients received
myeloablative conditioning followed by mobilized peripheral-blood stem-cell
transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours
starting the day before transplantation until day 14 after transplantation.
RESULTS: A total of 36 patients who could be evaluated, with a median age of 46
years (range, 20 to 59), received transplants from matched related or unrelated
donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of
grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the
incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality
was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD
were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free,
relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were
similar to those seen in patients undergoing allogeneic stem-cell
transplantation.
CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with
tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute
GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell
transplantation. (Funded by the National Heart, Lung, and Blood Institute;
ClinicalTrials.gov number, NCT02683525.).

Copyright © 2021 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa2027372
PMCID: PMC7845486
PMID: 33406328 [Indexed for MEDLINE]

Conflict of interest statement: Disclosure forms provided by the authors are

available with the full text of this article at NEJM.org.

20. Am Heart J. 2022 Jan;243:167-176. doi: 10.1016/j.ahj.2021.08.012. Epub 2021 Sep

15.

Rationale and Design of the Groningen Intervention Study for the Preservation of
Cardiac Function with Sodium Thiosulfate after St-segment Elevation Myocardial
Infarction (GIPS-IV) trial.

de Koning ML(1), van Dorp P(2), Assa S(2), Hartman MH(2), Voskuil M(3), Anthonio
RL(4), Veen D(5), Pundziute-Do Prado G(2), Leiner T(6), van Goor H(7), van der
Meer P(2), van Veldhuisen DJ(2), Nijveldt R(8), Lipsic E(2), van der Harst P(9).

Author information:
(1)Department of Cardiology, University of Groningen, University Medical Center
Groningen, Groningen, the Netherlands. Electronic address:
[email protected].
(2)Department of Cardiology, University of Groningen, University Medical Center
Groningen, Groningen, the Netherlands.
(3)Department of Cardiology, Division of Heart & Lungs, University Medical
Center Utrecht, Utrecht, the Netherlands.
(4)Department of Cardiology, Treant hospital location Scheper, Emmen, the
Netherlands.
(5)Department of Methodology and Statistics, University Medical Center Utrecht,
Utrecht, the Netherlands.
(6)Department of Radiology, University Medical Center Utrecht, Utrecht, the
Netherlands.
(7)Department of Pathology and Medical Biology, University of Groningen,
University Medical Center Groningen, Groningen, the Netherlands.
(8)Department of Cardiology, Radboud University Medical Center, Nijmegen, the
Netherlands.
(9)Department of Cardiology, University of Groningen, University Medical Center
Groningen, Groningen, the Netherlands; Department of Cardiology, Division of
Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.

BACKGROUND: Ischemia and subsequent reperfusion cause myocardial injury in

patients presenting with ST-segment elevation myocardial infarction (STEMI).
Hydrogen sulfide (H2S) reduces "ischemia-reperfusion injury" in various
experimental animal models, but has not been evaluated in humans. This trial
will examine the efficacy and safety of the H2S-donor sodium thiosulfate (STS)
in patients presenting with a STEMI.
STUDY DESIGN: The Groningen Intervention study for the Preservation of cardiac
function with STS after STEMI (GIPS-IV) trial (NCT02899364) is a double-blind,
randomized, placebo-controlled, multicenter trial, which will enroll 380
patients with a first STEMI. Patients receive STS 12.5 grams intravenously or
matching placebo in addition to standard care immediately at arrival at the
catheterization laboratory after providing consent. A second dose is
administered 6 hours later at the coronary care unit. The primary endpoint is
myocardial infarct size as quantified by cardiac magnetic resonance imaging 4
months after randomization. Secondary endpoints include the effect of STS on
peak CK-MB during admission and left ventricular ejection fraction and NT-proBNP
levels at 4 months follow-up. Patients will be followed-up for 2 years to assess
clinical endpoints.
CONCLUSIONS: The GIPS-IV trial is the first study to determine the effect of a
H2S-donor on myocardial infarct size in patients presenting with STEMI.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.ahj.2021.08.012
PMID: 34534493 [Indexed for MEDLINE]

21. Am J Transplant. 2018 Jan;18(1):258-261. doi: 10.1111/ajt.14461. Epub 2017 Sep

26.

In situ liver splitting under extracorporeal membrane oxygenation in brain-dead

donor.

Assalino M(1), Majno P(1)(2), Toso C(1), Berney T(1), Giraud R(3), Dutkowski
P(4), Andres A(1), Wildhaber B(5), Elkrief L(1).

Author information:
(1)Division of Transplantation, Department of Surgery, University Hospitals,
Geneva, Switzerland.
(2)HPB Center, University Hospitals of Geneva, Geneva, Switzerland.
(3)Intensive Care University Hospitals, Geneva, Switzerland.
(4)Division of Transplantation, University Hospital, Zurich, Switzerland.
(5)University Center of Pediatric Surgery of Western Switzerland, University
Hospitals, Geneva, Switzerland.

Hemodynamic instability is generally considered as a contraindication to liver

splitting, in particular when using an in situ technique. We describe the cases
of two young donors with brain death in whom refractory cardiac arrest and
hemodynamic instability were supported by veno-arterial extracorporeal membrane
oxygenation (VA-ECMO), allowing uneventful in situ splitting. Two adult and two
pediatric liver recipients were successfully transplanted with immediate graft
function. Favorable outcomes were also observed for the other transplanted
organs, including one heart, two lungs, and four kidneys. Refractory cardiac
arrest and hemodynamic instability corrected by VA-ECMO should not be considered
as a contraindication to in situ liver splitting.

© 2017 The American Society of Transplantation and the American Society of

Transplant Surgeons.

DOI: 10.1111/ajt.14461
PMID: 28801937 [Indexed for MEDLINE]

22. Am J Transplant. 2018 Sep;18(9):2148-2162. doi: 10.1111/ajt.14876. Epub 2018

May
28.

Pediatric heart transplantation across a positive crossmatch: First year results

from the CTOTC-04 multi-institutional study.

Webber S(1), Zeevi A(2), Mason K(3), Addonizio L(4), Blume E(5), Dipchand A(6),
Shaddy R(7), Feingold B(8), Canter C(9), Hsu D(10), Mahle W(11), Armstrong B(3),
Morrison Y(12), Ikle D(3), Diop H(12), Odim J(12); CTOTC-04 Investigators.
Author information:
(1)Department of Pediatrics, Vanderbilt University School of Medicine,
Nashville, TN, USA.
(2)Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh,
PA, USA.
(3)Rho Federal Systems Division, Chapel Hill, NC, USA.
(4)Division of Pediatric Cardiology, Columbia University Medical Center, New
York, NY, USA.
(5)Department of Pediatric Cardiology, Boston Children's Hospital, Boston, MA,
USA.
(6)Department of Paediatrics, Hospital for Sick Children, Labatt Family Heart
Center, Toronto, Ontario, Canada.
(7)Division of Pediatric Cardiology, Children's Hospital of Philadelphia,
Philadelphia, PA, USA.
(8)Department of Pediatrics, University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA.
(9)Division of Pediatric Cardiology, Washington University School of Medicine,
St. Louis, MO, USA.
(10)Division of Pediatric Cardiology, Albert Einstein College of
Medicine/Children's Hospital at Montefiore, Bronx, NY, USA.
(11)Division of Pediatric Cardiology, Children's Healthcare of Atlanta, Atlanta,
GA, USA.
(12)Transplantation Branch, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD, USA.

Comment in
Am J Transplant. 2018 Sep;18(9):2107-2108. doi: 10.1111/ajt.14986.

Sensitization is common in pediatric heart transplant candidates and waitlist

mortality is high. Transplantation across a positive crossmatch may reduce wait
time, but is considered high risk. We prospectively recruited consecutive
candidates at eight North American centers. At transplantation, subjects were
categorized as nonsensitized or sensitized (presence of ≥1 HLA antibody with MFI
≥1000 using single antigen beads). Sensitized subjects were further classified
as complement-dependent cytotoxicity crossmatch (CDC-crossmatch) positive or
negative and as donor-specific antibodies (DSA) positive or negative.
Immunosuppression was standardized. CDC-crossmatch-positive subjects also
received perioperative antibody removal, maintenance corticosteroids, and
intravenous immunoglobulin. The primary endpoint was the 1 year incidence rate
of a composite of death, retransplantation, or rejection with hemodynamic
compromise. 317 subjects were screened, 290 enrolled and 240 transplanted (51
with pretransplant DSA, 11 with positive CDC-crossmatch). The incidence rates of
the primary endpoint did not differ statistically between groups; nonsensitized
6.7% (CI: 2.7%, 13.3%), sensitized crossmatch positive 18.2% (CI: 2.3%, 51.8%),
sensitized crossmatch negative 10.7% (CI: 5.7%, 18.0%), P = .2354. The primary
endpoint also did not differ by DSA status. Freedom from antibody-mediated and
cellular rejection was lower in the crossmatch positive group and/or in the
presence of DSA. Follow-up will determine if acceptable outcomes can be achieved
long-term.

© 2018 The American Society of Transplantation and the American Society of

Transplant Surgeons.

DOI: 10.1111/ajt.14876
PMID: 29673058 [Indexed for MEDLINE]

23. Lancet Respir Med. 2018 May;6(5):357-367. doi: 10.1016/S2213-2600(18)30136-X.

Epub 2018 Apr 9.

Normothermic ex-vivo preservation with the portable Organ Care System Lung
device for bilateral lung transplantation (INSPIRE): a randomised, open-label,
non-inferiority, phase 3 study.

Warnecke G(1), Van Raemdonck D(2), Smith MA(3), Massard G(4), Kukreja J(5), Rea
F(6), Loor G(7), De Robertis F(8), Nagendran J(9), Dhital KK(10), Moradiellos
Díez FJ(11), Knosalla C(12), Bermudez CA(13), Tsui S(14), McCurry K(15), Wang
IW(16), Deuse T(17), Lesèche G(18), Thomas P(19), Tudorache I(20), Kühn C(20),
Avsar M(20), Wiegmann B(21), Sommer W(21), Neyrinck A(2), Schiavon M(6),
Calabrese F(6), Santelmo N(4), Olland A(4), Falcoz PE(4), Simon AR(8), Varela
A(11), Madsen JC(22), Hertz M(23), Haverich A(21), Ardehali A(24).

Author information:
(1)Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery,
Hannover Medical School, Hannover, Germany; German Center for Lung Research
(DZL; partner site), Hannover, Germany. Electronic address:
[email protected].
(2)Department of Thoracic Surgery, University Hospital Leuven, Leuven, Belgium.
(3)Department of General Thoracic Surgery, St Joseph's Medical Center, Phoenix,
AZ, USA.
(4)Department of Thoracic Surgery, Hospital of University of Strasbourg,
Strasbourg, France.
(5)Department of Thoracic Surgery, University of California San Francisco, San
Francisco, CA, USA.
(6)Department of Thoracic Surgery, University of Padua, Padua, Italy.
(7)Department of Cardiothoracic Surgery, University of Minnesota, Minneapolis,
MN, USA.
(8)Department of Cardiothoracic Surgery, Royal Brompton and Harefield Hospital
Trust, London, UK.
(9)Department of Surgery, Division of Cardiac Surgery, University of Alberta
Medical Center, Edmonton, AB, Canada.
(10)Department of Cardiothoracic Surgery, St Vincent's Hospital, Sydney, NSW,
Australia.
(11)Department of Thoracic Surgery, University Hospital Puerta de Hierro,
Madrid, Spain.
(12)Department of Cardiothoracic and Vascular Surgery, German Heart Institute
Berlin, Berlin, Germany; German Centre for Cardiovascular Research (DHZK;
partner site), Berlin, Germany.
(13)Department of Cardiothoracic Surgery, University of Pittsburgh Medical
Center, Pittsburgh, PA, USA.
(14)Cardiothoracic Surgery, Papworth Hospital Trust, Papworth, UK.
(15)Cardiothoracic Surgery, The Cleveland Clinic Foundation, Cleveland, OH, USA.
(16)Department of Cardiothoracic Surgery, Indiana University, Indianapolis, IN,
USA.
(17)Department Cardiovascular Surgery, University Hospital Eppendorf, Hamburg,
Germany.
(18)Department Thoracic and Vascular Surgery, Hospital Bichat, Paris, France.
(19)Department of Thoracic Surgery, Lung Transplantation, and Diseases of the
Esophagus, University Hospitals of Marseille, Marseille, France.
(20)Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery,
Hannover Medical School, Hannover, Germany.
(21)Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery,
Hannover Medical School, Hannover, Germany; German Center for Lung Research
(DZL; partner site), Hannover, Germany.
(22)Massachusetts General Transplant Center and Department of Cardiac Surgery,
Massachusetts General Hospital, Boston, MA, USA.
(23)Department of Respiratory Medicine, University of Minnesota, Minneapolis,
MN, USA.
(24)Department of Surgery, Division of Cardiothoracic Surgery, Ronald Reagan
University of California, Los Angeles Medical Center, Los Angeles, CA, USA.

Erratum in
Lancet Respir Med. 2018 Jun;6(6):e27. doi: 10.1016/S2213-2600(18)30207-8.

Comment in
Lancet Respir Med. 2018 May;6(5):319-320. doi:
10.1016/S2213-2600(18)30144-9.

BACKGROUND: Severe primary graft dysfunction (PGD) of grade 3 (PGD3) is a common

serious complication following lung transplantation. We aimed to assess
physiological donor lung preservation using the Organ Care System (OCS) Lung
device compared with cold static storage.
METHODS: In this non-inferiority, randomised, controlled, open-label, phase 3
trial (INSPIRE) recipients were aged 18 years or older and were registered as
standard criteria primary double lung transplant candidates. Eligible donors
were younger than 65 years old with a ratio of partial pressure of oxygen in
arterial blood to the fraction of inspired oxygen of more than 300 mm Hg.
Transplant recipients were randomly assigned (1:1) with permuted blocks,
stratified by centre, to receive standard criteria donor lungs preserved in the
OCS Lung device (OCS arm) or cold storage at 4°C (control arm). The composite
primary effectiveness endpoint was absence of PGD3 within the first 72 h after
transplant and 30-day survival in the per-protocol population, with a stringent
4% non-inferiority margin. Superiority was tested upon meeting non-inferiority.
The primary safety endpoint was the mean number of lung graft-related serious
adverse events within 30 days of transplant. We did analyses in the per-protocol
and intention-to-treat populations. This trial is registered with
ClinicalTrials.gov, number NCT01630434.
FINDINGS: Between Nov 17, 2011, and Nov 24, 2014, we randomly assigned 370
patients, and 320 (86%) underwent transplantation (n=151 OCS and n=169 control);
follow-up was completed in Nov 24, 2016. The primary endpoint was met in 112
(79·4%) of 141 patients (95% CI 71·8 to 85·8) in the OCS group compared with 116
(70·3%) of 165 patients (62·7 to 77·2) in the control group (non-inferiority
point estimate -9·1%; 95% CI -∞ to -1·0; p=0·0038; and superiority test
p=0·068). Patient survival at day 30 post-transplant was 135 (95·7%) of 141
patients (95% CI 91·0-98·4) in the OCS group and 165 patients (100%; 97·8-100·0)
in the control group (p=0·0090) and at 12 months was 126 (89·4%) of 141 patients
(83·1-93·9) for the OCS group compared with 146 (88·1%) of 165 patients
(81·8-92·8) for the control group. Incidence of PGD3 within 72 h was reported in
25 (17·7%) of 141 patients in the OCS group (95% CI 11·8 to 25·1) and 49 (29·7%)
of 165 patients in the control group (22·8 to 37·3; superiority test p=0·015).
The primary safety endpoint was met (0·23 lung graft-related serious adverse
events in the OCS group compared with 0·28 events in the control group [point
estimate -0·045%; 95% CI -∞ to 0·047; non-inferiority test p=0·020]). In the
intention-to-treat population, causes of death at 30 days and in hospital were
lung graft failure or lung infection (n=2 for OCS vs n=7 for control), cardiac
causes (n=4 vs n=1), vascular or stroke (n=3 vs n=0), metabolic coma (n=0 vs
n=2), and generalised sepsis (n=0 vs n=1).
INTERPRETATION: The INSPIRE trial met its primary effectiveness and safety
endpoints. Although no short-term survival benefit was reported, further
research is needed to see whether the reduced incidence of PGD3 within 72 h of a
transplant might translate into earlier recovery and improved long-term outcomes
after lung transplantation.
FUNDING: TransMedics Inc.

Copyright © 2018 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S2213-2600(18)30136-X
PMID: 29650408 [Indexed for MEDLINE]

24. Reprod Biol Endocrinol. 2017 Feb 7;15(1):10. doi: 10.1186/s12958-017-0228-7.

The Human Oocyte Preservation Experience (HOPE) Registry: evaluation of

cryopreservation techniques and oocyte source on outcomes.

Nagy ZP(1), Anderson RE(2), Feinberg EC(3), Hayward B(4), Mahony MC(4).

Author information:
(1)Reproductive Biology Associates, 1100 Johnson Ferry Rd #200, Atlanta, GA,
30342, USA. [email protected].
(2)Southern California Center for Reproductive Medicine, 361 Hospital Rd #333,
Newport Beach, CA, 92663, USA.
(3)Fertility Centers of Illinois, 67 Park Ave W #190, Highland Park, IL, 60035,
USA.
(4)EMD Serono, Inc., One Technology Pl., Rockland, MA, 02370, USA.

BACKGROUND: This prospective, Phase IV, multicenter, observational registry of

assisted reproductive technology clinics in the USA studied outcomes of first
cycles using thawed/warmed cryopreserved (by slow-freezing/vitrification)
oocytes (autologous or donor).
METHODS: Patients were followed up through implantation, clinical pregnancy, and
birth outcomes. The main outcome measure was live birth rate (LBR), defined as
the ratio of live births to oocytes thawed/warmed minus the number of embryos
cryopreserved for each cycle, averaged over all thawing cycles. Clinical
pregnancy rate (CPR) was also evaluated, and was defined as the presence of a
fetal sac with heart activity, as detected by ultrasound scan performed on Day
35-42 after embryo transfer.
RESULTS: A total of 16 centers enrolled 204 patients; data from 193 patients
were available for analyses. For donor oocytes, in the slow-freezing (n = 40)
versus vitrification (n = 94) groups, respectively, CPR and LBR were
significantly different: 32.4% versus 62.6%, and 25.0% versus 52.1%; outcomes
from Day 3 transfers did not differ significantly. For vitrified oocytes, in the
autologous (n = 46) versus donor (n = 94) group, respectively, CPR and LBR were
significantly different: 30.0% versus 62.6% and 17.4% versus 52.1%. This was
largely due to a significant difference in CPR with Day 5/6 transfers.
CONCLUSIONS: In two subgroup data analyses, in women who received cryopreserved
oocytes from donors, CPR and LBR were significantly higher in cycles using
oocytes cryopreserved via vitrification versus slow-freezing, reflecting
differences in methodologies and more Day 5/6 transfers; in women who received
vitrified oocytes, CPR and LBR were significantly higher in cycles using donor
versus autologous oocytes with Day 5/6 transfers.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT00699400 . Registered June 13, 2008.

DOI: 10.1186/s12958-017-0228-7
PMCID: PMC5296964
PMID: 28173814 [Indexed for MEDLINE]

25. Liver Transpl. 2018 Oct;24(10):1336-1345. doi: 10.1002/lt.25301.

Donor Dopamine Does Not Affect Liver Graft Survival: Evidence of Safety From a
Randomized Controlled Trial.

Benck U(1), Jung M(1), Krüger B(1), Grimm A(1), Weiss C(2), Yard BA(1), Lehner
F(3), Kiessling A(4), Fischer L(5), Gallinat A(6), Kleespies A(7), Lorf T(8),
Sucher R(9), Mönch C(10), Scherer MN(11), Rahmel A(12), Schemmer P(13), Krämer
BK(1), Schnuelle P(1)(14).

Author information:
(1)Vth Department of Medicine, University Medical Center Mannheim.
(2)Department of Biomathematics and Medical Statistics, Medical Faculty
Mannheim, University of Heidelberg, Heidelberg, Germany.
(3)Clinic for General, Abdominal and Transplant Surgery, Hannover Medical
School, Hannover, Germany.
(4)Department of Abdominal, Visceral and Transplantation Surgery, Charité
University Medicine, Berlin, Germany.
(5)Department of Hepatobiliary and Transplant Surgery, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany.
(6)Department of General, Visceral, and Transplantation Surgery, University
Hospital Essen, University of Duisburg-Essen, Essen, Germany.
(7)Department of General, Visceral, Vascular and Transplant Surgery, Klinikum
Grosshadern, Ludwig Maximilians University of Munich, Munich, Germany.
(8)Department of General, Visceral and Pediatric Surgery, University Medical
Center Göttingen, Georg August University, Göttingen, Germany.
(9)Department of Visceral, Transplantation, Thoracic and Vascular Surgery,
University Hospital Leipzig, Germany.
(10)Department of General, Visceral and Transplantation Surgery,
Westpfalz-Klinikum, Kaiserslautern, Germany.
(11)Department of Surgery and Transplantation, University Hospital Regensburg,
Regensburg, Germany.
(12)German Organ Transplantation Foundation, Frankfurt, Germany.
(13)Division of Transplant Surgery, Department of Surgery, Medical University of
Graz, Graz, Austria.
(14)Center for Renal Diseases, Weinheim, Germany.

Treatment of donation after brain death (DBD) donors with low-dose dopamine
improves the outcomes after kidney and heart transplantation. This study
investigates the course of liver allografts from multiorgan donors enrolled in
the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov
identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were
randomly assigned to receive low-dose dopamine. Dopamine was infused at 4
μg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5
hours). We assessed the outcomes of 212 liver transplantations (LTs) performed
at 32 European centers. Donors and recipients of both groups were very similar
in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver
Disease score was not different in recipients of a dopamine-treated versus
untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was
10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in
biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of
hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early
retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary
nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4%
versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus
62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus
78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In
conclusion, donor pretreatment with dopamine has no short-term or longterm
effects on outcome after LT. Therefore, low-dose dopamine pretreatment can
safely be implemented as the standard of care in hemodynamically stable DBDs.

© 2018 by the American Association for the Study of Liver Diseases.

DOI: 10.1002/lt.25301
PMID: 30102825 [Indexed for MEDLINE]
26. Stem Cells Transl Med. 2017 Nov;6(11):1963-1971. doi: 10.1002/sctm.17-0040.
Epub
2017 Sep 7.

Cryopreserved Off-the-Shelf Allogeneic Adipose-Derived Stromal Cells for Therapy

in Patients with Ischemic Heart Disease and Heart Failure-A Safety Study.

Kastrup J(1)(2)(3), Haack-Sørensen M(2)(3), Juhl M(2)(3), Harary Søndergaard

R(2)(3), Follin B(2)(3), Drozd Lund L(2)(3), Mønsted Johansen E(1)(3), Ali
Qayyum A(1)(3), Bruun Mathiasen A(1)(3), Jørgensen E(1)(3), Helqvist S(1)(3),
Jørgen Elberg J(4), Bruunsgaard H(5), Ekblond A(2)(3).

Author information:
(1)Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark.
(2)Cardiology Stem Cell Centre, Rigshospitalet, University of Copenhagen,
Denmark.
(3)The Heart Centre, Rigshospitalet, University of Copenhagen, Denmark.
(4)Department of Plastic Surgery, Breast Surgery & Burns, Rigshospitalet,
University of Copenhagen, Denmark.
(5)Department of Clinical Immunology, Rigshospitalet, University of Copenhagen,
Denmark.

The present first-in-human clinical trial evaluated the safety and feasibility
of a newly developed and cryopreserved Cardiology Stem Cell Centre
adipose-derived stromal cell (CSCC_ASC) product from healthy donors for
intramyocardial injection in ten patients with ischemic heart disease and
ischemic heart failure (IHF). Batches of CSCC_ASC were isolated from three
healthy donors by liposuction from abdominal adipose tissue. Adipose mesenchymal
stromal cells were culture expanded in bioreactors without the use of animal
constituents, cryopreserved, and stored in vials in nitrogen dry-storage
containers until use. Direct injection of CSCC_ASC into the myocardium did not
cause any complications or serious adverse events related to either treatment or
cell administration in a 6-month follow-up period. Four out of ten heart failure
patients developed donor-specific de novo human leukocyte antigen (HLA) class I
antibodies, and two out of ten patients had donor-specific HLA antibodies
already at baseline. There were no clinical symptoms or changes in inflammatory
parameters in the follow-up period that indicated an ongoing immune response.
There was a tendency toward improvement in cardiac function after CSCC_ASC
treatment at 6-month follow-up: left ventricular end systolic volume decreased
and left ventricular ejection fraction increased. In addition, exercise capacity
increased. These changes were independent of the presence or absence of HLA
antibodies. It is concluded that the newly developed cryopreserved product
CSCC_ASC from healthy donors was a safe and feasible treatment. We observed a
tendency toward efficacy in patients with IHF. These findings have to be
confirmed in larger placebo controlled clinical trials. Stem Cells Translational
Medicine 2017;6:1963-1971.

© 2017 The Authors Stem Cells Translational Medicine published by Wiley

Periodicals, Inc. on behalf of AlphaMed Press.

DOI: 10.1002/sctm.17-0040
PMCID: PMC6430047
PMID: 28880460 [Indexed for MEDLINE]

Conflict of interest statement: J.K., A.E., and M.H.S. have filed an

International (PCT) patent application No. PCT/EP2016/075407 “Stem cell therapy
in patients with ischenmic heart disease”. H.B. has received honoraria for a
lecture. The other authors indicated no potential conflicts of interest.
27. Clin Transplant. 2017 Jun;31(6). doi: 10.1111/ctr.12982. Epub 2017 Apr 21.

Graft-derived macrophage migration inhibitory factor correlates with

hepatocellular injury in patients undergoing liver transplantation.

Baron-Stefaniak J(1), Schiefer J(1), Miller EJ(2), Plöchl W(1), Krenn CG(1),
Berlakovich GA(3), Baron DM(1), Faybik P(1).

Author information:
(1)Department of Anesthesia, General Intensive Care and Pain Management, Medical
University of Vienna, Vienna, Austria.
(2)Heart and Lung Research Center, The Feinstein Institute for Medical Research,
Manhasset, NY, USA.
(3)Department of Surgery, Division of Transplantation, Medical University of
Vienna, Vienna, Austria.

Experimental studies suggest that macrophage migration inhibitory factor (MIF)

mediates ischemia/reperfusion injury during liver transplantation. This study
assessed whether human liver grafts release MIF during preservation, and whether
the release of MIF is proportional to the extent of hepatocellular injury.
Additionally, the association between MIF and early allograft dysfunction (EAD)
after liver transplantation was evaluated. Concentrations of MIF, aspartate
aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase
(LDH), and creatine kinase (CK) were measured in effluents of 38 liver grafts,
and in serum of recipients. Concentrations of MIF in the effluent were greater
than those in the recipients' serum before and after reperfusion (58
[interquartile range, IQR:23-79] μg/mL vs 0.06 [IQR:0.03-0.07] μg/mL and 1.3
[IQR:0.7-1.8] μg/mL, respectively; both P<.001). Effluent MIF concentrations
correlated with effluent concentrations of the cell injury markers ALT (R=.51,
P<.01), AST (R=.51, P<.01), CK (R=.45, P=.01), and LDH (R=.56, P<.01). Patients
who developed EAD had greater MIF concentrations in effluent and serum 10
minutes after reperfusion than patients without EAD (Effluent: 80 [IQR:63-118]
μg/mL vs 36 [IQR:20-70] μg/mL, P=.02; Serum: 1.7 [IQR:1.2-2.5] μg/mL vs 1.1
[IQR:0.6-1.7] μg/mL, P<.001).
CONCLUSION: Human liver grafts release MIF in proportion to hepatocellular
injury. Greater MIF concentrations in effluent and recipient's serum are
associated with EAD after liver transplantation.

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

DOI: 10.1111/ctr.12982
PMID: 28370484 [Indexed for MEDLINE]

28. Am J Surg. 2018 May;215(5):802-803. doi: 10.1016/j.amjsurg.2017.12.015. Epub

2018 Jan 4.

Retro-peritoneal cooling for kidney preservation from multi-organ cadaver

donors.

Salazar-Bañuelos A(1), Monroy-Cuadros M(2), Henriquez-Cooper H(3).

Author information:
(1)Department of Surgery, Division of Transplant Surgery, University of Calgary,
Faculty of Medicine, 1403-29 Street NW, Calgary, AB, Canada. Electronic address:
[email protected].
(2)Department of Surgery, Division of Transplant Surgery, University of Calgary,
Faculty of Medicine, 1403-29 Street NW, Calgary, AB, Canada. Electronic address:
[email protected].
(3)Department of Surgery, Division of Transplant Surgery, University of Calgary,
Faculty of Medicine, 1403-29 Street NW, Calgary, AB, Canada. Electronic address:
[email protected].

Comment in
Am J Surg. 2018 May;215(5):804. doi: 10.1016/j.amjsurg.2017.11.053.

BACKGROUND: Minimizing ischemia is paramount in the procurement of kidneys for

transplantation. A fast cooling and expeditious removal is ideal to minimize
damage from warm ischemia, however, since the removal of kidneys is delayed in
cadaver donation until all other organs are harvested, the risk of kidney damage
increases due to contact with the warmer soft body tissues. Surgical techniques
that expedite organ retrieval were developed to avoid organ damage.
METHODS: We test a modification of Thomas Starzl's improved technique for
multi-organ harvesting by interposing an ice bag between the posterior aspect of
the kidney and the psoas muscle in a randomized trial with 21 multi-organ
cadaver donors.
RESULTS: The modified technique decreases the extraction temperature of the
kidneys significantly in comparison with the controls, p < .001.
CONCLUSIONS: This simple technique improves the preservation of kidneys from
cadaver donors, and can potentially have more impact on multi-organ donation
after cardiac death.

Copyright © 2018 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.amjsurg.2017.12.015
PMID: 29317046 [Indexed for MEDLINE]

29. Medicine (Baltimore). 2018 Sep;97(38):e11879. doi: 10.1097/MD.0000000000011879.

Factors influencing the contamination rates of the conjunctival swabs and organ
culture media of human donor eyes.

Röck T(1), Landenberger J, Buhl M, Yoeruek E, Bartz-Schmidt KU, Bramkamp M,

Blumenstock G, Röck D.

Author information:
(1)Centre for Ophthalmology Institute of Medical Microbiology and Hygiene,
University of Tübingen, Tübingen Department of General Medicine, Ruhr-University
Bochum, Bochum Institute for Clinical Epidemiology and Applied Biometry,
University of Tübingen, Tübingen, Germany.

Erratum in
Medicine (Baltimore). 2018 Oct;97(41):e12852. doi:
10.1097/MD.0000000000012852.

This study assessed the influence of donor, environmental, and logistical

factors on the contamination rates of the conjunctival swabs and organ culture
media of human donor eyes.In total, 1008 conjunctival swabs and 418 organ
culture media samples from 504 consecutive human donor eyes were analyzed.
Cross-tabulation, chi-squared tests, and Fisher's exact tests were used to
assess the influence of the different factors on the contamination rates of the
conjunctival swabs and organ culture media.The overall contamination rates were
28.4% for the conjunctival swabs and 1.0% for the organ culture media. A
prolonged time between death and the conjunctival swab collection was associated
with an increased conjunctival swab contamination rate [odds ratio (OR) = 1.9,
95% confidence interval (CI) = 1.2-3.0, P = .007]. The highest conjunctival swab
contamination rate was found in the corneas procured in external institutions
(outside the university hospital) (44.1%, OR = 3.6, 95%CI = 1.5-8.4, P = .003).
Hospitalization times of 2 to 7 days prior to death were associated with an
increased conjunctival swab contamination risk (OR = 2.6, 95%CI = 1.1-5.8,
P = .021). However, the sex, age, cause of donor death, differentiation between
septic and aseptic donors, differentiation between heart-beating brain-dead
multiorgan donors and cadaveric donors, a warmer mean monthly temperature, and
death to corneoscleral disc excision time did not significantly increase the
conjunctival swab contamination risk. In addition, none of these factors
affected the organ culture media contamination risk. Moreover, a positive
conjunctival swab did not significantly increase the media contamination risk
(P = .08). Surprisingly, the microorganisms causing media contamination were
present at 50% of the amount detected on the conjunctival surface of the
respective donor eye.A prolonged time between death and the conjunctival swab
collection, a hospitalization time of 2 to 7 days prior to death, and corneal
collection outside the university hospital seemed to be the main factors
responsible for an increased conjunctival swab contamination risk. In addition,
our investigation illustrated that a positive conjunctival swab is not a strong
indicator for organ culture media contamination. Critical discussion is
necessary regarding the validity of conjunctival swabs as prognostic parameters
for organ culture media contamination.

DOI: 10.1097/MD.0000000000011879
PMCID: PMC6160100
PMID: 30235655 [Indexed for MEDLINE]

Conflict of interest statement: The authors have no conflicts of interest to

disclose.

30. Ann Thorac Surg. 2017 Nov;104(5):e383-e384. doi:

10.1016/j.athoracsur.2017.05.087.

Coronary Dissection Discovered During Ex Vivo Organ Preservation: Avoiding

a Fatal Complication.

Sponga S(1), Napgal D(2), Beltrami AP(3), Ferrara V(4), Nalon S(4), Finato N(3),
Livi U(4).

Author information:
(1)Cardiothoracic Department, University Hospital of Udine, Udine, Italy.
Electronic address: [email protected].
(2)Department of Surgery, Western University, London, Ontario, Canada.
(3)Department of Medicine, University of Udine, Udine, Italy.
(4)Cardiothoracic Department, University Hospital of Udine, Udine, Italy.

This report describes the case of undiagnosed posttraumatic coronary artery

dissection in a young multiorgan donor. Ex vivo preservation with the Organ Care
System (TransMedics, Inc, Andover, MA) revealed the presence of coronary disease
and avoided transplantation of an organ at high risk for failure.

Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc.

All rights reserved.

DOI: 10.1016/j.athoracsur.2017.05.087
PMID: 29054234 [Indexed for MEDLINE]
31. Lancet Respir Med. 2019 Nov;7(11):975-984. doi: 10.1016/S2213-2600(19)30200-0.
Epub 2019 Aug 1.

Portable normothermic ex-vivo lung perfusion, ventilation, and functional

assessment with the Organ Care System on donor lung use for transplantation from
extended-criteria donors (EXPAND): a single-arm, pivotal trial.

Loor G(1), Warnecke G(2), Villavicencio MA(3), Smith MA(4), Kukreja J(5),
Ardehali A(6), Hartwig M(7), Daneshmand MA(7), Hertz MI(8), Huddleston S(9),
Haverich A(2), Madsen JC(3), Van Raemdonck D(10).

Author information:
(1)Department of Cardiothoracic Surgery, University of Minnesota, Minneapolis,
MN, USA; Baylor College of Medicine, Baylor St Luke's Medical Center, Houston,
TX, USA. Electronic address: [email protected].
(2)Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery,
Hannover Medical School, Hannover, Germany.
(3)Massachusetts General Transplant Center and Department of Cardiac Surgery,
Massachusetts General Hospital, Boston, MA, USA.
(4)Department of General Thoracic Surgery, St Joseph's Medical Center, Phoenix,
AZ, USA.
(5)Department of Thoracic Surgery, University of California San Francisco, San
Francisco, CA, USA.
(6)Department of Surgery, Division of Cardiothoracic Surgery, Ronald Reagan
University of California, Los Angeles Medical Center, Los Angeles, CA, USA.
(7)Division of Cardiovascular and Thoracic Surgery, Duke University Medical
Center, Durham, NC, USA.
(8)Department of Pulmonary, Allergy, Critical Care and Sleep Medicine,
University of Minnesota, Minneapolis, MN, USA.
(9)Department of Cardiothoracic Surgery, University of Minnesota, Minneapolis,
MN, USA.
(10)Department of Thoracic Surgery, University Hospitals Leuven, Leuven,
Belgium.

Comment in
Lancet Respir Med. 2019 Nov;7(11):925-926. doi:
10.1016/S2213-2600(19)30245-0.

BACKGROUND: Donor lung use for transplantation is the lowest among solid organ
tranplants because of several complex and multifactorial reasons; one area that
could have a substantial role is the limited capabilities of cold ischaemic
storage. The aim of the EXPAND trial was to evaluate the efficacy of
normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on
donor lung use from extended-criteria donors and donors after circulatory death,
which are rarely used.
METHODS: In this single-arm, pivotal trial done in eight institutions across the
USA, Germany, and Belgium, lungs from extended-criteria donors were included if
fulfilling one or more of the following criteria: a ratio of partial pressure of
arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (FiO2)
in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h;
donor age 55 years or older; or lungs from donors after circulatory death that
were recruited and assessed using OCS Lung. Lungs were transplanted if they
showed stability of OCS Lung variables, PaO2:FiO2 was more than 300 mm Hg, and
they were accepted by the transplanting surgeon. Patients were adult bilateral
lung transplant recipients. The primary efficacy endpoint was a composite of
patient survival at day 30 post-transplant and absence of The International
Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3)
within 72 h post-transplantation, with a prespecified objective performance goal
of 65%. The primary analysis population was all transplanted recipients. This
trial is registered with ClinicalTrials.gov, number NCT01963780, and is now
complete.
FINDINGS: Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused,
ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS
transplantation criteria so 81 lungs were suitable for transplantation. Two
lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs
were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients
and did not meet the objective performance goal. 35 (44%) of 79 patients had
PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days
post-transplant. The mean number of lung graft-related serious adverse events
(respiratory failure and major pulmonary-related infection) was 0·3 events per
patient (SD 0·5).
INTERPRETATION: Despite missing the objective primary endpoint, the portable OCS
Lung resulted in 87% donor lung use for transplantation with excellent clinical
outcomes. Many lungs declined by other transplant centres were successfully
transplanted using this new technology, which implies its use has the potential
to increase the number of lung transplants performed worldwide. Whether similar
outcomes could be obtained if these lungs were preserved on ice is unknown and
remains an area for future research.
FUNDING: TransMedics Inc.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S2213-2600(19)30200-0
PMID: 31378427 [Indexed for MEDLINE]

32. Amino Acids. 2017 Jul;49(7):1193-1202. doi: 10.1007/s00726-017-2420-7. Epub

2017
Apr 20.

Low plasma homoarginine concentration is associated with high rates of all-cause

mortality in renal transplant recipients.

Kayacelebi AA(1), Minović I(2), Hanff E(1), Frenay AS(3), de Borst MH(2),
Feelisch M(4), van Goor H(3), Bakker SJL(2), Tsikas D(5).

Author information:
(1)Centre of Pharmacology and Toxicology, Hannover Medical School,
Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
(2)Nephrology, University Medical Center Groningen and University of Groningen,
Groningen, The Netherlands.
(3)Pathology and Medical Biology, University Medical Center Groningen and
University of Groningen, Groningen, The Netherlands.
(4)Clinical and Experimental Sciences, Faculty of Medicine, NIHR Southampton
Biomedical Research Centre, University of Southampton and University Hospital
Southampton NHS Foundation Trust, Southampton, UK.
(5)Centre of Pharmacology and Toxicology, Hannover Medical School,
Carl-Neuberg-Str. 1, 30625, Hannover, Germany. [email protected].

In renal transplant recipients (RTR), we recently found that low urinary

excretion of homoarginine (hArg) is associated with mortality and graft failure.
However, it is not known whether such prospective associations also hold true
for plasma concentrations of hArg. In the present study, we therefore determined
plasma concentrations of hArg in the same cohort, i.e. in 687 RTR (functioning
graft ≥1 year), and in 140 healthy donors, before and after kidney donation.
Plasma hArg concentrations were significantly lower in RTR compared to healthy
controls [1.24 (0.95-1.63) µM vs. 1.58 (1.31-2.03) µM, P < 0.001], and kidney
donation resulted in a decrease in plasma hArg concentration to 1.41
(1.10-1.81) µM (P < 0.001). In RTR, multivariable linear regression analysis
revealed BMI (β = 0.124), heart rate (β = -0.091), pre-emptive transplantation
(β = 0.078), antidiabetic medication (β = -0.091), eGFR (β = 0.272), plasma PTH
(β = -0.098), uric acid (β = 0.137), alkaline phosphatase (β = -0.100), HDL
(β = -0.111), NT-pro-BNP (β = -0.166), and urinary urea excretion (β = 0.139) as
main determinants of plasma hArg (all P < 0.05). In RTR, plasma hArg
concentration was inversely associated with all-cause [hazard ratio (HR) 0.59
(95% CI 0.50-0.70), P < 0.001] and cardiovascular mortality [HR 0.50
(0.39-0.66), P < 0.001], both expressed per standard deviation change in
log-transformed hArg, independent of potential confounders. To conclude, our
results suggest that the kidney is a major hArg production site and an important
modulator of hArg homeostasis in the renal and cardiovascular systems. Moreover,
low plasma hArg is independently associated with increased risk of
cardiovascular mortality in RTR, which corroborates the cardiovascular
importance of preserving kidney function after transplantation.

DOI: 10.1007/s00726-017-2420-7
PMID: 28429125 [Indexed for MEDLINE]

33. Transfusion. 2018 Apr;58(4):905-916. doi: 10.1111/trf.14528. Epub 2018 Mar 1.

Red blood cells treated with the amustaline (S-303) pathogen reduction system: a
transfusion study in cardiac surgery.

Brixner V(1), Kiessling AH(2), Madlener K(3), Müller MM(1), Leibacher J(1),
Dombos S(1), Weber I(1), Pfeiffer HU(1), Geisen C(1), Schmidt M(1), Henschler
R(4)(5), North A(6), Huang N(6), Mufti N(6), Erickson A(6), Ernst C(6), Rico
S(6), Benjamin RJ(6), Corash LM(6), Seifried E(1).

Author information:
(1)Institute for Transfusion Medicine and Immunohematology of Johann Wolfgang
Goethe University and German Red Cross Blood Donor Service, Frankfurt am Main,
Germany.
(2)Department of Thoracic and Cardiovascular Surgery, Johann Wolfgang Goethe
University Hospital Frankfurt, Frankfurt am Main, Germany.
(3)Department of Haemostaseology and Transfusion Medicine, Kerckhoff-Klinik, Bad
Nauheim, Germany.
(4)Blood Center Zürich, Swiss Red Cross, Schlieren, Switzerland.
(5)Red Cross Blood Service Graubünden, Chur, Switzerland.
(6)Cerus Corporation, Concord, California.

BACKGROUND: Nucleic acid-targeted pathogen inactivation technology using

amustaline (S-303) and glutathione (GSH) was developed to reduce the risk of
transfusion-transmitted infectious disease and transfusion-associated
graft-versus-host disease with red blood cell (RBC) transfusion.
STUDY DESIGN AND METHODS: A randomized, double-blind, controlled study was
performed to assess the in vitro characteristics of amustaline-treated RBCs
(test) compared with conventional (control) RBCs and to evaluate safety and
efficacy of transfusion during and after cardiac surgery. The primary device
efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs.
Exploratory clinical outcomes included renal and hepatic failure, the 6-minute
walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and
the immune response to amustaline-treated RBCs.
RESULTS: A total of 774 RBC unis were produced. Mean treatment difference in Hb
content was -2.27 g/unit (95% confidence interval, -2.61 to -1.92 g/unit),
within the prespecified equivalence margins (±5 g/unit) to declare
noninferiority. Amustaline-treated RBCs met European guidelines for Hb content,
hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received
study RBCs. There were no significant differences in RBC usage or other clinical
outcomes. Observed AEs were within the spectrum expected for patients of similar
age undergoing cardiovascular surgery requiring RBCs transfusion. No patients
exhibited an immune response specific to amustaline-treated RBCs.
CONCLUSION: Amustaline-treated RBCs demonstrated equivalence to control RBCs for
Hb content, have appropriate characteristics for transfusion, and were well
tolerated when transfused in support of acute anemia. Renal impairment was
characterized as a potential efficacy endpoint for pivotal studies of RBC
transfusion in cardiac surgery.

© 2018 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of

AABB.

DOI: 10.1111/trf.14528
PMID: 29498049 [Indexed for MEDLINE]

34. Clin Immunol. 2017 Apr;177:18-28. doi: 10.1016/j.clim.2015.11.005. Epub 2015

Nov
18.

NK cell compartment in the peripheral blood and spleen in adult patients with
primary immune thrombocytopenia.

Ebbo M(1), Audonnet S(2), Grados A(1), Benarous L(1), Mahevas M(3), Godeau B(3),
Viallard JF(4), Piperoglou C(2), Cognet C(2), Farnarier C(2), Harlé JR(1),
Schleinitz N(1), Vély F(5).

Author information:
(1)Département de Médecine Interne, Hôpital Timone Adulte, Assistance Publique -
Hôpitaux de Marseille, Aix-Marseille Université, 13005 Marseille, France.
(2)Immunologie, Hôpital de la Conception, Assistance Publique - Hôpitaux de
Marseille, Aix-Marseille Université, 13005 Marseille, France.
(3)Department of Internal Medicine, National Referral Center For Adult Immune
Cytopenias, Henri-Mondor University Hospital, Assistance Publique - Hôpitaux de
Paris, Université Paris-Est Créteil, 51 Av. du Mal de Lattre de Tassigny, 94010
Créteil cedex, France.
(4)Département de Médecine Interne, CHU de Bordeaux-GH Sud, Hôpital Haut-Lévêque
1 avenue Magellan, 33604 Pessac cedex, France.
(5)Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University UM2,
Inserm, U1104, CNRS UMR7280, 13288 Marseille, France; Immunologie, Hôpital de la
Conception, Assistance Publique - Hôpitaux de Marseille, Aix-Marseille
Université, 13005 Marseille, France. Electronic address: [email protected].

Immune thrombocytopenic purpura (ITP) is a disease characterized by

antibody-mediated platelet destruction. The T- and B-cell subsets have been
extensively studied in primary ITP, but the NK cell compartment has been less
thoroughly explored. We investigated the NK cell receptor repertoire and the
functionality of NK cells in the peripheral blood and spleen in patients with
primary ITP. An immunophenotypic analysis of peripheral blood lymphocytes from
patients revealed that the numbers of CD19+ B lymphocytes, CD4+ and CD8+ T
lymphocytes and CD3-CD56+ NK cells were within the normal range. No major
alteration to the expression of distinct inhibitory or activating NK cell
receptors was observed. The functionality of NK cells, as evaluated by their
ability to degranulate in conditions of natural cytotoxicity or
antibody-dependent cell cytotoxicity (ADCC), was preserved in these patients. By
contrast, these stimuli induced lower levels of IFNγ production by the NK cells
of ITP patients than by those of healthy controls. We then compared the splenic
NK cell functions of ITP patients with those of cadaveric heart-beating donors
(CHBD) as controls. The splenic NK cells of ITP patients tended to be less
efficient in natural cytotoxicity conditions and more efficient in ADCC
conditions than control splenic NK cells. Finally, we found that infusions of
intravenous immunoglobulin led to the inhibition of NK cell activation through
the modulation of the interface between target cells and NK cells.

Copyright © 2015. Published by Elsevier Inc.

DOI: 10.1016/j.clim.2015.11.005
PMID: 26598010 [Indexed for MEDLINE]

35. Transfusion. 2018 Feb;58(2):317-322. doi: 10.1111/trf.14425. Epub 2017 Nov 28.

Evaluation of the applicability and effectiveness of a molecular strategy for

identifying weak D and DEL phenotype among D- blood donors of mixed origin
exhibiting high frequency of RHD*Ψ.

Dezan MR(1), Guardalini LGO(1), Pessoa E(1), Ribeiro IH(1), Oliveira VB(1), Luz
F(1), Novac DR(1), Gallucci A(1), Bonifácio S(1), Gomes F(1), Levi JE(1),
Pereira AC(2), Krieger JE(2), Mendrone-Junior A(1), Rocha V(1)(3), Dinardo
CL(1)(2).

Author information:
(1)Immunohematology Division, Fundação Pró-Sangue, Hemocentro de São Paulo.
(2)Laboratory of Genetics and Molecular Cardiology, Heart Institute (InCor),
University of São Paulo School of Medicine.
(3)Discipline of Hematology, University of São Paulo School of Medicine, São
Paulo, Brazil.

BACKGROUND: Molecular tests designed to detect the presence of active RHD gene
among D- donors have been successfully applied in people of European ancestry,
but not in admixed populations with a considerable frequency of RHD*Ψ. Our goal
was to evaluate the performance of a molecular screening tool for identifying
active RHD alleles among Brazilian blood donors classified as D- C+ and/or E+.
STUDY DESIGN AND METHODS: Pools of five DNA samples of serologically D- C+
and/or E+ donors were checked by a RHD polymerase chain reaction (PCR) assay
specific for RHD Intron 4 and Exon 7. When a pool result was positive, samples
were genotyped individually for RHD Intron 4 and Exon 7, RHD*Ψ, RHCE*Cc, and RHD
zygosity. Donors suspected of active RHD gene were further evaluated by
whole-coding region and flanking intron direct sequencing.
RESULTS: A total of 405 donors were included. Two percent exhibited active RHD
gene, codifying D-weak (38 and 45) or DEL phenotype. The most prevalent DEL
allele was RHD*DEL1 (c.1227G>A), which is proven to be immunogenic. A high
frequency of RHD*Ψ was detected in the donors with nondeleted RHD alleles (31%),
far superior to the frequency of RHD variant alleles (15.5%). The proposed
approach presented sensitivity of 100% and specificity of 85.7% for identifying
active RHD gene.
CONCLUSION: The strategy of checking D- donors with RHD PCR followed by
exclusion of RHD*Ψ allele has proved efficient in identifying weak-D and DEL
phenotype in the Brazilian population.

© 2017 AABB.

DOI: 10.1111/trf.14425
PMID: 29193119 [Indexed for MEDLINE]

36. Br J Anaesth. 2017 May 1;118(5):689-698. doi: 10.1093/bja/aex083.

Randomized trial of red cell washing for the prevention of
transfusion-associated organ injury in cardiac surgery.

Wozniak MJ(1), Sullo N(1), Qureshi S(1), Dott W(1), Cardigan R(2), Wiltshire
M(2), Morris T(3), Nath M(1), Bittar N(4), Bhudia SK(5), Kumar T(1), Goodall
AH(1), Murphy GJ(1).

Author information:
(1)Department of Cardiovascular Sciences and NIHR Cardiovascular Biomedical
Research Unit, University of Leicester, Glenfield Hospital, Leicester LE3 9QP,
UK.
(2)National Health Service Blood and Transplant, Cambridge CB2 0PT, UK.
(3)Leicester Clinical Trials Unit, Leicester Diabetes Centre, Leicester General
Hospital, Leicester LE5 4PW, UK.
(4)Blackpool Victoria Hospital NHS Trust, Blackpool, Lancashire FY3 8NR, UK.
(5)University Hospitals Coventry and Warwickshire NHS Trust, Clifford Bridge
Road, Coventry CV2 2DX, UK.

BACKGROUND: Experimental studies suggest that mechanical cell washing to remove

pro-inflammatory components that accumulate in the supernatant of stored donor
red blood cells (RBCs) might reduce inflammation and organ injury in transfused
patients.
METHODS: Cardiac surgery patients at increased risk of large-volume RBC
transfusion were eligible. Participants were randomized to receive either
mechanically washed allogenic RBCs or standard care RBCs. The primary outcome
was serum interleukin-8 measured at baseline and at four postsurgery time
points. A mechanism substudy evaluated the effects of washing on stored RBCs in
vitro and on markers of platelet, leucocyte, and endothelial activation in trial
subjects.
RESULTS: Sixty adult cardiac surgery patients at three UK cardiac centres were
enrolled between September 2013 and March 2015. Subjects received a median of
3.5 (interquartile range 2-5.5) RBC units, stored for a mean of 21 ( sd
5.2) days, within 48 h of surgery. Mechanical washing reduced concentrations of
RBC-derived microvesicles but increased cell-free haemoglobin concentrations in
RBC supernatant relative to standard care RBC supernatant. There was no
difference between groups with respect to perioperative serum interleukin-8
values [adjusted mean difference 0.239 (95% confidence intervals -0.231, 0.709),
P =0.318] or concentrations of plasma RBC microvesicles, platelet and leucocyte
activation, plasma cell-free haemoglobin, endothelial activation, or biomarkers
of heart, lung, or kidney injury.
CONCLUSIONS: These results do not support a hypothesis that allogenic red blood
cell washing has clinical benefits in cardiac surgery.
CLINICAL TRIAL REGISTRATION: ISRCTN 27076315.

© The Author 2017. Published by Oxford University Press on behalf of the British
Journal of Anaesthesia.

DOI: 10.1093/bja/aex083
PMCID: PMC5430295
PMID: 28475670 [Indexed for MEDLINE]

37. BMC Nephrol. 2015 Jun 9;16:81. doi: 10.1186/s12882-015-0076-7.

Exaggerated blood pressure response to dynamic exercise despite chronic

refractory hypotension: results of a human case study.

Rogan A(1), McGregor G(2)(3), Weston C(4), Krishnan N(5), Higgins R(6), Zehnder
D(7)(8), Ting SM(9)(10).

Author information:
(1)Departments of Renal Medicine and Transplantation, University Hospital
Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX,
UK. [email protected].
(2)Departments of Renal Medicine and Transplantation, University Hospital
Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX,
UK. [email protected].
(3)Departments of Cardiac Exercise Physiology, University Hospital Coventry and
Warwickshire NHS Trust, Coventry, UK. [email protected].
(4)Department of Nephrology, Dorset County Hospital NHS Foundation Trust,
Dorchester, UK. [email protected].
(5)Departments of Renal Medicine and Transplantation, University Hospital
Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX,
UK. [email protected].
(6)Departments of Renal Medicine and Transplantation, University Hospital
Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX,
UK. [email protected].
(7)Departments of Renal Medicine and Transplantation, University Hospital
Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX,
UK. [email protected].
(8)Division of Metabolic and Vascular Health, The University of Warwick,
Coventry, UK. [email protected].
(9)Departments of Renal Medicine and Transplantation, University Hospital
Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX,
UK. [email protected].
(10)Division of Metabolic and Vascular Health, The University of Warwick,
Coventry, UK. [email protected].

BACKGROUND: Chronic refractory hypotension is a rare but significant mortality

risk in renal failure patients. Such aberrant physiology usually deems patient
unfit for renal transplant surgery. Exercise stimulates the
mechano-chemoreceptors in the skeletal muscle thereby modulating the sympathetic
effects on blood pressure regulation. The haemodynamic response to dynamic
exercise in such patients has not been previously investigated. We present a
case with severe chronic hypotension who underwent exercise testing before and
after renal transplantation, with marked differences in blood pressure response
to exercise.
CASE PRESENTATION: A 40-year old haemodialysis-dependent patient with a 2 year
history of refractory hypotension (≤80/50 mmHg) was referred for living donor
renal transplantation at our tertiary centre. Each dialysis session was often
less than 2 h and 30 min due to symptomatic hypotension. As part of the
cardiovascular assessment, she underwent haemodynamic evaluation with
cardiopulmonary exercise testing. Blood pressure normalized during unloaded
pedalling but was exaggerated at maximal workload whereby it rose from
82/50 mmHg to a peak of 201/120 mmHg. Transthoracic echocardiography, tonometric
measure of central vascular compliance and myocardial perfusion scan were
normal. She subsequently underwent an antibody-incompatible renal
transplantation and was vasopressor reliant for 14 days during the
post-operative period. Eight weeks following transplant, resting blood pressure
was normal and a physiological exercise-haemodynamic response was observed
during a repeat cardiopulmonary exercise testing.
CONCLUSION: This case highlights the potential therapeutic role of unloaded leg
cycling exercise during dialysis session to correct chronic hypotension,
allowing patients to have greater tolerance to fluid shift. It also adds to
existing evidence that sympathetic dysfunction is reversible with renal
transplant. Furthermore chronic hypotension with preserved exercise-haemodynamic
response and cardiovascular reserve should not preclude these patients from
renal transplant surgery.

DOI: 10.1186/s12882-015-0076-7
PMCID: PMC4460705
PMID: 26055191 [Indexed for MEDLINE]