This book is an edited collection on the topic of myocardial protection during cardiac surgery. It contains 34 chapters written by experts in the field covering the history and current strategies for protecting the heart during procedures. The editors are Tomas A. Salerno and Marco Ricci from the University of Miami.

2. Myocardial Protection

3. This book is dedicated to our wives
Michelle Ricci and
Helen Salerno

4. MyocardialT
Protection
EDITED BY
Tomas A. Salerno, MD
Professor and Chief
Division of Cardiothoracic Surgery
University of Miami
Jackson Memorial Hospital
Miami, Florida
and
Marco Ricci, MD
Assistant Professor of Surgery
Division of Cardiothoracic Surgery
Staff Surgeon, Section of Pediatric Cardiac Surgery
University of Miami
Jackson Memorial Hospital
Miami, Florida
Blackwell
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5. © 2004 by Futura, an imprint of Blackwell Publishing
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0304050654321
ISBN: 1-4051-1643-9
Library of Congress Cataloging-in-Publication Data
Myocardial protection / edited by Tomas A. Salerno and Marco
Ricci. — Isted.
p.; cm.
Includes bibliographical references and index.
ISBN 1-4051-1643-9
1. Heart—Surgery—Complications—Prevention. 2. Myocardium.
3. Cardiac arrest, Induced. 4. Myocardial reperfusion. 5. Re-perfusion
injury—Prevention. I. Salerno, Tomas A. II. Ricci,
Marco, M.D.
[DNLM: 1. Cardiovascular Surgical Procedures—methods.
WG168M99582004]
RD598.M9152004
617.4'l-dc21
2003009294
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6. Contents
List of Contributors, vii 9 Intermittent Antegrade Warm Blood
Cardioplegia, 75
Foreword, xi
Antonio Maria Calafiore, MD, Giuseppe Vitolla,
W. Gerard Rainer, MD
MD, and Angela laco, MD
Preface, xii
10 Antegrade, Retrograde, or Both?, 82
1 The History of Myocardial Protection, 1 Frank G. Scholl, MD and Davis C. Drinkwater, MD
Anthony L Panos, MD, MSc, FRCSC, FACS
11 Miniplegia: Biological Basis, Surgical Techniques,
2 The Duality of Cardiac Surgery: Mechanical and and Clinical Results, 88
Metabolic Objective, 13 Giuseppe D'Ancona, MD, Hratch Karamanoukian,
Gerald D. Buckberg, MD MD, LuigiMartinelli, MD, Michael O. Sigler, MD,
and TomasA. Salerno, MD
3 Modification of Ischemia-Reperfusion-Induced
Injury by Cardioprotective Interventions, 18 12 Substrate Enhancement in Cardioplegia, 94
Ming Zhang, MD, Tamer Sallam, BS, BA, Yan-Jun Shafie Fazel, MD, Marc P. Pelletier, MD, and
Xu, PhD, andNaranjan S. Dhalla, PhD, MD Bernard S. Goldman, MD
(Hon), DSc (Hon)
13 Is There a Place for On-Pump, Beating Heart
4 Anesthetic Preconditioning: A New Horizon in Coronary Artery Bypass Grafting Surgery? The
Myocardial Protection, 33 Pros and Cons, 119
Nader D. Nader, MD, PhD, FCCP Simon Fortier, MD, Roland G. Demaria, MD,
5 Myocardial Protection During Acute Myocardial PhD, FETCS, and Louis P. Perrault, MD, PhD,
Infarction and Angioplasty, 43 FRCSC, FACS
Alexandre C. Ferreira, MD, FACC and Eduardo 14 Myocardial Protection in Beating Heart Coronary
deMarchena, MD, FACC Artery Surgery, 126
6 Intermittent Aortic Cross-Clamping for Vinod H. Thourani, MD and John D. Puskas,
Myocardial Protection, 53 MD, MSc
Fabio Biscegli Jatene, MD, PhD, Paulo M.
15 Beating Heart Coronary Artery Bypass Grafting:
Pego-Fernandes, MD, PhD, and Alexandre
Intraoperative Strategies to Avoid Myocardial
Ciappina Hueb, MD
Ischemia, 134
7 Intermittent Warm Blood Cardioplegia: The Kushagra Katariya, MD, Michael O. Sigler, MD
Biochemical Background, 59 and Tomas A. Salerno, MD
Ganghong Tian, MD, PhD, TomasA. Salerno, MD,
16 Beating Heart Coronary Artery Bypass in Patients
and Roxanne Deslauriers, PhD
with Acute Myocardial Infarction: A New Strategy
8 Warm Heart Surgery, 70 to Protect the Myocardium, 144
Hassan Tehrani, MB, BCh, Atiq Rehman, MD, Jan F. Gummert, MD, PhD, Michael A. Borger,
Pierluca Lombardi, MD, Mohan Thanikachalam, MD, PhD, Ardawan Rastan, MD, and Friedrich W.
MD, and Tomas Salerno, MD Mohr, MD, PhD

7. VI Contents
17 Beating Heart Coronary Artery Bypass with 27 Myocardial Preconditioning in the Experimental
Continuous Perfusion Through the Coronary Model: A New Strategy to Improve Myocardial
Sinus, 152 Protection, 230
Harinder Singh Bedi, MCh, FIACS Eliot R. Rosenkranz, MD, Jun Feng, MD, PhD,
and Hong-Ling Li, MD, MSc
18 On-Pump Beating Heart Surgery for Dilated
Cardiomyopathy and Myocardial Protection, 160 28 New Concepts in Myocardial Protection in
Tadashi Isomura, MD and Hisayoshi Suma, MD Pediatric Cardiac Surgery, 264
Bindu Bittira, MD, MSc, Dominique Shum-Tim,
19 Myocardial Protection with Beta-Blockers in
MD, MSc, and Christo I. Tchervenkov, MD
Valvular Surgery, 167
Nawwar Al Attar, FRCS, MSc, FETCS, Marcio 29 Extracardiac Fontan: The Importance of Avoiding
Scorsin, MD, PhD, andArrigo Lessana, MD, FETCS Cardioplegic Arrest, 275
Carlo F. Marcelletti, MD and Raul F. Abella,
20 Myocardial Protection in Minimally Invasive
MD
Valvular Surgery, 174
Rene Pretre, MD and Marko I. Turina, MD 30 Preservative Cardioplegic Solutions in Cardiac
Transplantation: Recent Advances, 282
21 Intermittent Warm Blood Cardioplegia in Aortic
Romualdo J. Segurola Jr., MD and Rosemary F.
Valve Surgery: An Update, 181
Kelly, MD
M. Saadah Suleiman, PhD, Raimondo Ascione,
MD, and Gianni D. Angelini, MD, FRCS 31 Myocardial Preservation in Clinical Cardiac
Transplantation: An Update, 292
22 Myocardial Protection in Surgery of the
Louis B. Louis IV, MD, Xiao-Shi Qi, MD, PhD,
Aortic Root, 189
and Si M. Pham, MD, FACS
Stephen Westaby, PhD, MS, FETCS
32 Myocardial Protection During Left Ventricular
23 Myocardial Protection in Major Aortic
Assist Device Implantation, 301
Surgery, 193
Aftab R. Kherani, MD, Mehmet C. Oz, MD, and
Marc A. Schepens, MD, PhD and Andrea Nocchi,
YoshifumiNaka, MD, PhD
MD
33 Gene Therapy for Myocardial Protection, 304
24 Recent Advances in Myocardial Protection for
Said F. Yassin, MD and Christopher G. McGregor,
Coronary Reoperations, 196
MD
Jan T. Christenson, MA, MD, PhD, PD, FETCS and
Afksendiyos Kalangos, MD, PhD, PD, FETCS 34 Aortic and Mitral Valve Surgery on the Beating
Heart, 311
25 Myocardial Protection During Minimally Invasive
Marco Ricci, MD, Pierluca Lombardi, MD, Michael
Cardiac Surgery, 203
O. Sigler, MD, Giuseppe D'Ancona, MD and
Saqib Masroor, MD, MHS and Kushagra Katariya,
TomasA. Salerno, MD
MD
Index, 321
26 Current Concepts in Pediatric Myocardial
Protection, 207
Bradley S. Allen, MD

8. List of Contributors
Raul F. Abel la, MD Jan T. Christenson, MA, MD, PHD,
Consultant in Cardiac Surgery, Division of Pediatric PD, FETCS
Cardiovascular Surgery, Ospedale Civico di Palermo, Chief of Clinic, Department of Surgery, Clinic for
Palermo, Sicily, Italy Cardiovascular Surgery, University Hospital of Geneva,
Geneva, Switzerland
Nawwar Al Attar, FRCS,
MSc, FETCS Giuseppe D'Ancona, MD
Cardiac Surgeon, Department of Cardiac Surgery, Hospital San Martino Geneva, University of Geneva
Centre Cardiologique du Nord, St. Denis, France Medical School, Geneva, Italy
Bradley S. Allen, MD Eduardo deMarchena, MD, FACC
Professor of Medicine and Surgery, Chief, Interventional
Chief, Division of Pediatric Cardiac Surgery, University of
Cardiology, University of Miami School of Medicine,
Texas, Houston; Memorial Hermann Children's Hospital,
Miami, FL, USA
Houston Texas, USA
Roland G. Demaria, MD, PHD, FETCS
Gianni D. Angelini, MD, FRCS Department of Surgery and Research Center, Montreal
Bristol Heart Institute, University of Bristol, Bristol, Heart Institute, Montreal, Quebec, Canada
United Kingdom
Roxanne Deslauriers, PHD
Raimondo Ascione, MD Director of Research, Institute for Biodiagnostics, National
Bristol Heart Institute, University of Bristol, Bristol, Research Council, Winnipeg, Manitoba, Canada
United Kingdom
Naranjan S. Dhalla, PHD, MD(Hon),
Harinder Singh Bedi, MCH, FIACS DSc (Hon)
Chief Cardiac Surgeon and Chairman, Cardiovascular Distinguished Professor and Director, Institute of
Surgery, Metro Heart Institute, Noida, New Delhi, India Cardiovascular Sciences, St. Boniface General Hospital
Research Centre, Winnipeg, Manitoba, Canada
Bindu Bittira, MD, MSC
Chief Resident, Thoracic Surgery, Division of Davis C. Drinkwater, MD
Cardiothoracic Surgery, The Montreal General Hospital, Department of Cardiothoracic Surgery, Vanderbilt
McGill University, Montreal, Quebec, Canada University Medical Center, Nashville, TN, USA
Michael A. Borger, MD, PHD Shaf ie Fazel, MD
Leipzig Heart Center, University of Leipzig, Leipzig, Resident, Division of Cardiac Surgery, University of
Germany Toronto, Toronto, Ontario, Canada
Gerald D. Buckberg, MD Alexandre C. Ferreira, MD, FACC
Division of Thoracic and Cardiovascular Surgery, Assistant Professor of Medicine, Coordinator,
University of California, Los Angeles, Los Angeles, Interventional Training Program, University of Miami
CA, USA School of Medicine, Miami, FL
Antonio Maria Calaf iore, MD Simon Fortier, MD
Professor and Chief, Department of Cardiac Surgery, Department of Surgery and Research Center, Montreal
"G. D'Annunzio" Chieti University, Chieti, Italy Heart Institute, Montreal, Quebec, Canada
VII

9. VIM List of Contributors
Bernard S. Goldman, MD Pierluca Lombard!, MD
Surgeon, Division of Cardiovascular Surgery, Sunnybrook Fellow in Cardiothoracic Surgery, Division of
and Women's College Health Sciences Centre, Toronto; Cardiothoracic Surgery, Daughtry Family Department of
Professor, Department of Surgery, University of Toronto, Surgery, University of Miami, Miami, FL, USA
Toronto, Ontario, Canada; Editor-in-Chief, Journal of
Cardiac Surgery Louis B. Louis IV, MD
Division of Cardiothoracic Surgery, University of Miami
Jan F. Gummert, MD, PHD School of Medicine, Miami, FL, USA
Leipzig Heart Center, University of Leipzig, Leipzig,
Germany Carlo F. Marcel letti, MD
Cardiovascular Surgeon-in-Chief, Division of Pediatric
Cardiovascular Surgery, Ospedale Civico di Palermo,
Alexandre Ciappina Hueb, MD
Department of Thoracic and Cardiovascular Surgery, Palermo, Sicily, Italy
Heart Institute, University of Sao Paulo, Sao Paulo,
Brazil Luigi Martinelli, MD
Hospital San Martino Genova, University of Geneva
Medical School, Genova, Italy
Angela lacd, MD
Staff Surgeon, Department of Cardiac Surgery, "G.
D'Annunzio" Chieti University, Chieti, Italy
Saqib Masroor, MD, MHS
Division of Thoracic and Cardiovascular Surgery, University
of Miami, Jackson Memorial Hospital, Miami, FL, USA
Tadashi Isomura, MD
Director, Cardiovascular Surgery, Hayama Heart Center,
Hayama, Kanagawa, Japan
Christopher G. McGregor, MD
Mayo Clinic Foundation, Rochester, MN, USA
Fabio Biscegli Jatene, MD, PHD Friedrich W. Mohr, MD, PHD
Department of Thoracic and Cardiovascular Surgery, Leipzig Heart Center, University of Leipzig, Leipzig,
Heart Institute, University of Sao Paulo, Sao Paulo, Brazil Germany
Af ksendiyos Kalangos, MD, PHD, Nader D. Nader, MD, PHD, FCCP
PD, FETCS Associate Professor of Anesthesiology, Surgery, Pathology,
Chief of Service, Department of Surgery, Clinic for and Anatomical Sciences, State University of New York at
Cardiovascular Surgery, University Hospital of Geneva, Buffalo; Chief, Perioperative Care and Anesthesia, Upstate
Geneva, Switzerland VA Healthcare System, Buffalo, NY, USA
Hratch Karamanoukian, MD Yoshifumi Naka, MD, PHD
Center for Less Invasive and Robotic Heart Surgery, Kaleida Herbert Irving Assistant Professor of Surgery, Director,
Health, Buffalo, NY, USA Mechanical Circulatory Support, Columbia University,
College of Physicians and Surgeons, New York, NY, USA
Kushagra Katariya, MD Andrea Nocchi, MD
Division of Cardiothoracic Surgery, University of Miami,
Cardiothoracic Surgeon, Department of Cardiac Surgery,
Jackson Memorial Hospital, Miami, FL, USA
Ospedale Carlo Poma, Mantova, Italy
Rosemary F. Kelly, MD Mehmet C. Oz, MD
Assistant Professor of Surgery, University of Minnesota, Associate Professor of Surgery, Director, The Cardiovascular
Cardiovascular and Thoracic Surgery, Minneapolis, MN, Institute, Columbia University, College of Physicians and
USA Surgeons, New York, NY, USA
Aftab R. Kherani, MD Anthony L. Panos, MD, MSC, FRCSC,
Resident in General Surgery, Duke University Medical FACS
Center, Durham, NC; Research Fellow, Division of Division of Cardiothoracic Surgery, William S. Middleton
Cardiothoracic Surgery, Columbia University, College of VA Medical Center; Associate Professor, University of
Physicians and Surgeons, New York, NY, USA Wisconsin at Madison, Madison, WI, USA
Arrigo Lessana, MD, FETCS Paulo M. Pego-Fernandes, MD, PHD
Chief of Surgery, Department of Cardiac Surgery, Centre Department of Thoracic and Cardiovascular Surgery, Heart
Cardiologique du Nord, St. Denis, France Institute, University of Sao Paulo, Sao Paulo, Brazil

10. List of Contributors IX
Marc P. Pel letter, MD Tamer Sal lam, BS, BA
Surgeon, Division of Cardiovascular Surgery, Sunnybrook Research Fellow, Institute of Cardiovascular Sciences, St.
and Women's College Health Sciences Centre, Toronto; Boniface General Hospital Research Centre, Winnipeg,
Assistant Professor, Department of Surgery, University of Manitoba, Canada
Toronto, Toronto, Ontario, Canada
Marc A. Schepens, MD, PHD
Louis P. Perrault, MD, PHD, FRCSC, FACS Department of Cardiothoracic Surgery, St. Antonius
Department of Surgery and Research Center, Montreal Hospital, Nieuwegein, The Netherlands
Heart Institute, Montreal, Quebec, Canada
Frank G. Scholl, MD
Department of Cardiothoracic Surgery, Vanderbilt
Si M. Pham, MD, FACS
University Medical Center, Nashville, TN, USA
Director, Section of Cardiopulmonary Transplantation,
Division of Cardiothoracic Surgery, University of Miami
School of Medicine, Miami, FL Marcio Scorsin, MD, PHD
Cardiac Surgeon, Department of Cardiac Surgery, Centre
Cardiologique du Nord, St. Denis, France
Rene Pretre, MD
Cardiovascular Surgery, University Hospital Zurich, Zurich,
Switzerland
Romualdo J. Segurola Jr., MD
Cardiovascular and Thoracic Surgery, University of
Minnesota, Minneapolis, MN, USA
John D. Puskas, MD, MSC
Associate Professor of Surgery, Carlyle Fraser Heart Center, Michael O. Sigler, MD
Division of Cardiothoracic Surgery, Department of Surgery, Department of Surgery, University of Miami, Jackson
Emory University School of Medicine, Atlanta, GA, USA Memorial Hospital, Miami, FL, USA
Xiao-Shi Qi, MD, PHD Dominique Shum-Tim, MD, MSC
Division of Cardiothoracic Surgery, University of Miami Staff Surgeon, The Montreal Children's Hospital; Staff
School of Medicine, Miami, FL, USA Surgeon, The Montreal General Hospital; Assistant
Professor of Surgery, McGill University, Montreal, Quebec,
W. Gerard Rainer, MD Canada
Distinguished Clinical Professor of Surgery, University of
Colorado Health Sciences Center; Past President and M. Saadah Suleiman, PHD
Historian, Society of Thoracic Surgeons Bristol Heart Institute, University of Bristol, Bristol, United
Kingdom
Ardawan Rastan, MD
Leipzig Heart Center, University of Leipzig, Leipzig, Hisayoshi Suma, MD
Germany Honored Director, Cardiovascular Surgery, Hayama Heart
Center, Hayama, Kanagawa, Japan
Atiq Rehman, MD
Fellow in Cardiothoracic Surgery, Division of Christo I. Tchervenkov, MD
Cardiothoracic Surgery, Daughtry Family Department of Director, Cardiovascular Surgery, The Montreal Children's
Surgery, University of Miami, Miami, FL, USA Hospital, Montreal, Quebec, Canada
Marco Ricci, MD Hassan Tehrani, MB, BCH
Fellow in Cardiothoracic Surgery, Division of
Assistant Professor of Surgery, Division of Cardiothoracic
Cardiothoracic Surgery, Daughtry Family Department of
Surgery, University of Miami, Jackson Memorial Hospital,
Surgery, University of Miami, Miami, FL, USA
Miami, FL, USA
Mohan Thanikachalam, MD
Eliot R. Rosenkranz, MD Fellow in Cardiothoracic Surgery, Division of
Director, Section of Pediatric Cardiac Surgery, Associate Cardiothoracic Surgery, Daughtry Family Department of
Professor of Surgery, University of Miami, Jackson Surgery, University of Miami, Miami, FL, USA
Memorial Hospital, Miami, FL, USA
Vinod H. Thourani, MD
Tomas A. Salerno, MD Resident in Cardiothoracic Surgery, Carlyle Fraser Heart
Professor and Chief, Division of Cardiothoracic Surgery Center, Division of Cardiothoracic Surgery, Department of
University of Miami, Jackson Memorial Hospital, Surgery, Emory University School of Medicine, Atlanta, GA,
Miami, FL, USA USA

11. List of Contributors
Ganghong Tian, MD, PHD Yan-Jun Xu, PHD
Associate Research Officer, Institute for Biodiagnostics, Research Scientist, Institute of Cardiovascular Sciences, St.
National Research Council, Winnipeg, Manitoba, Canada Boniface General Hospital Research Centre, Winnipeg,
Manitoba, Canada
Marko I. Turina, MD
Cardiovascular Surgery, University Hospital Zurich, Zurich, Said F. Yassin, MD
Switzerland Division of Cardiothoracic Surgery, University of Miami
School of Medicine, Miami, FL, USA
Giuseppe Vitolla, MD
Staff Surgeon, Department of Cardiac Surgery, Ming Zhang, MD
"G. D'Annunzio" Chieti University, Chieti, Italy Research Fellow, Institute of Cardiovascular Sciences, St.
Boniface General Hospital Research Centre, Winnipeg,
Stephen Westaby, PHD, MS, FETCS Manitoba, Canada
Oxford Heart Centre, John Radcliffe Hospital, Oxford,
United Kingdom

12. Foreword
When open heart surgery became a possibility one- Salerno and Ricci have admirably filled a needed
half century ago, it seems that considerable atten- niche by pulling together various approaches and
tion was directed toward protection of the body as a modalities for myocardial protection applicable to
whole (perhaps it was assumed that this would take many different scenarios—the chapter titles speak for
care of the needs of the heart as well). Hypothermia, themselves in exhibiting the array of situations dis-
partial perfusion, intermittent aortic cross-clamping cussed in detail along with au courant data regarding
and a variety of other techniques were thought to various methods of protection based upon pioneer-
suffice until careful observers noted occurrence of ing investigations by contributors such as Kirklin,
such events as "stone heart," subendocardial ischemia, Buckberg, and others.
and other manifestations of inadequate myocardial This volume is an absolute necessity for cardiac sur-
protection. This dramatically demonstrated that the geons in training and in practice and is so designed to
heart could not be treated as just any other organ or be an invaluable teaching tool and reference into the
part of the body. Its function is so different because of foreseeable future.
its intricate neuromuscular structure that investiga-
W. Gerard Rainer, MD
tions were begun (and continue until the present) to
Distinguished Clinical Professor of Surgery
define the cellular metabolic needs of the heart and to
University of Colorado Health Sciences Center
develop ways to meet those needs so that, hopefully,
Past President and Historian, Society
minimal cardiac function will be lost following correc-
of Thoracic Surgeons
tion of the underlying abnormality.
XI

13. Preface
Cardiac surgery has undergone major changes in the need to put together a collection of manuscripts writ-
recent past. With changes came new knowledge, tech- ten by experts in the different fields of myocardial pro-
nology and progress, all aimed at providing better tection. The idea is to give the reader an up-to-date
care to our patients. Fundamentally, however, cardiac view of how myocardial protective strategies are being
surgery "is myocardial protection," the realization utilized by surgeons performing different procedures.
that no matter how perfect the reparative surgery, Although it was recognized that the past plays a major
myocardial function has to be preserved for a short role in current methods of myocardial protection, the
and long-term successful outcome. The pace of tech- book was intentionally aimed at the present and the
nological advancements has accelerated over the last future.
five years, allowing surgeons to perform cardiac surgery The editors are grateful to all the authors and
differently and more comfortably. For each proced- co-authors who wrote this modern book. Their tasks
ure, there is the need for different technology, such as were time consuming, aside from their daily work as
devices, valves, suture materials, stabilizers, shunts, clinicians and scientists. It is a tribute to them that the
blowers, and others. One factor, however, has remained publishers were able to print a textbook that is up to
constant, i.e. the need for individualization for a date with current knowledge regarding myocardial
specific method of myocardial protection tailored to protection.
each operation.
TomasA. Salerno, MD
It is in this spirit that the editors of this book felt the
Marco Ricci, MD
XII

14. CHAPTER 1
The history of myocardial
protection
Anthony L Panos, MD, MSC, FRCSC, FAGS
outline of the work that has brought us to where we
Introduction
are today.
The history of myocardial protection is a rich and
varied story that encompasses the work of basic scient-
Early cardiac physiology
ists and clinicians working in different countries over
many years. It is an excellent example of clinical prob- The whole of biologic and medical sciences flowered
lems stimulating basic research and then translating at the end of the 19th century, as exemplified by the
that knowledge back "from the bench to the bedside." microbiologic discoveries of Pasteur, Koch's postul-
Many surgeons are aware of the famous quotation by ates, and Claude Bernard's emphasis on homeostasis
the great 19th century surgeon Theodore Billroth, that as a principle, to maintain the "internal milieu" [7].
"any surgeon who operates upon the heart, should There were also great advances in physiology, espe-
lose the respect of his colleagues." At the time that cially cardiac physiology and the understanding of
Billroth made that statement, cardiac surgery was muscle mechanics by Otto Frank [8-10], and Starling
indeed very hazardous because knowledge and tech- [11].
niques were not available to make it safe. The ensuing The pioneering work of Sydney Ringer on the
years saw a growth in knowledge and new technology effects of electrolytes on the regulation of the heart
that led to the development of modern cardiac surgery beat [12-15] is summarized by Toledo-Pereyra [16].
as we currently practice it. Physiologists in the late 19th century thought about
Myocardial protection was a key part of these control of cardiac function in terms of myogenic ver-
developments that allowed safe cardiac surgery to sus neurogenic theories. It was in this atmosphere that
be performed. The term myocardial protection en- Ringer conducted his elegant experiments and showed
compasses more than just cardioplegia, and can be the effects of various ions on the heartbeat. Ringer's
said to include things such as the perioperative man- work was initally not appreciated in Europe, but was
agement of patients with medical treatment (such followed by American physiologists, who extended it
as beta-blockers, etc.), or support devices (such as [17-21]. As early as 1935, Zwikster and Boyd had
intraaortic balloon pumps), better anesthetic agents, shown that the heart could be reversibly arrested using
and better hemodynamic management. All of these potassium [22]. However, surgeons did not appreciate
treatments contribute to making cardiac surgery this physiological research, and the clinical applica-
safer, and to get a sick patient through a major opera- tion of this knowledge would occur 20 years later.
tion. However, for the purposes of our discussion we Cardiovascular physiology continued to expand
will focus more on the development of cardioplegia. through the early years of the 20th century, but was
This is a very large field of research and has been carried on largely by zoologists, and physiologists
reviewed in several books [1-5] and review articles working on problems of basic science. For example,
[6]. In one chapter we will only be able to go over there were studies of the thebesian vein system that
some of the important highlights, and give a general would later become especially important to the

15. CHAPTER 1
technique of retrograde cardioplegia [23-31]. Others of mitral valve stenosis [57-59] or pulmonary valve
studied the electrophysiology [21,32] of the heart, stenosis [60]. There were a variety of ingenious opera-
the physiology of coronary blood flow [33-38], myo- tions done through artificial "wells," for example, to
cardial energetics [31,39-41], and the relationships allow closure of an atrial septal defect "underwater"
between coronary blood flow and cardiac mechanics [61].
[42-44]. All of this important basic science work was All of these operations reflected the limits of the
crucial to later clinical applications. technology of their time. Most were very ingenious,
and in many ways ahead of their time. However, in the
final analysis they all required the ability to support
Early operations—closed
the circulation to make the breakthroughs that they
Surgeons returned from the second world war after were seeking.
exposure to military surgery, and had developed an
interest in the treatment of traumatic chest wounds
Early operations—open
[45]. This renewed interest in cardiac surgery led to a
great expansion of the specialty in the 1950s. Cardiac Experimental work using inflow occlusion to allow
surgery developed later than other surgical specialties, work within the heart (i.e. "open" operations) found
largely due to the technical difficulties of operating on that brain injury occurred when the cerebral blood
the heart. The surgeon could not support the circula- flow was interrupted. The irreversible brain injury
tion while working on the heart, and this limited the occurred with interruptions of about 4 min duration.
kinds of surgery that could be done upon the heart. As Bigelow first proposed the use of hypothermia dur-
a result, the early operations for cardiac disease con- ing cardiac surgery in 1950 [62]. This led Bigelow,
sisted mostly of extracardiac procedures, such as the Swan, Boerema, and others to investigate the use
ligation of a patent ductus arteriosus by Gross and of hypothermia in cardiac surgery [39,62-71]. This
Hubbard [46], and the revolutionary work of Blalock laboratory work was then taken into the clinical world
and Taussig to create palliative shunts for the treat- and the first intracardiac repairs using systemic
ment of cyanotic congenital heart disease [47]. hypothermia were reported [67,69,70,72]. However,
There were other early attempts to operate on it is important to note that in these early papers the
the surface of the heart. These operations included original intention for the use of hypothermia was to
methods to treat ischemic heart disease by increas- protect primarily the brain, and not the heart.
ing the blood flow to the myocardium by creating In 1950 Bigelow found that in experimental models
noncoronary collateral blood supply to the heart. the total body oxygen consumption decreased with
Pericardial adhesions were created, for example, by temperature, and this included myocardial metabol-
means of pericardial irritation, or by covering the ism [62,63]. This data was later expanded and became
heart with omentum after epicardial and pericardial the rationale for the use of hypothermia as a technique
abrasion [48-50]. Some investigators studied the to protect the heart.
effects of coronary sinus ligation in animal models The crucial technology of artificial circulatory sup-
in an effort to impede venous outflow and thereby port was developed, principally by the perseverance of
improve coronary artery perfusion of myocardium Dr John Gibbon [73-75]. The "heart-lung machine"
[27-29,51]. Dr Claude Beck developed an operation of Gibbon could support the circulation, and this
to "revascularize" the heart using the cardiac venous development really allowed cardiac surgery to be done
system [48-50]. The Beck operation created a venous [76]. Surgeons could at last safely support the patient's
bypass to the epicardial veins of the heart and sub- circulation while working within the heart. However,
sequent ligation of the coronary sinus [52-56]. It is in order to provide the body's oxygen requirements,
remarkable how much Beck achieved with the limited high flow rates were needed. This was initially a dif-
technology available to him, and how prescient his ficult problem, and stressed the available technology
work was, predicting that surgery would become of early oxygenators. Investigators reassessed Bigelow's
important in the treatment of angina pectoris. earlier findings for total body oxygen consumption
There were also some closed operations performed, and temperature dependence. They found that by
such as mitral commissurotomy for the treatment adding hypothermia, the total body requirements for

16. History of myocardial protection
oxygen were greatly decreased in patients. Therefore, found that there was no ultrastructural damage
the total flow rates needed to provide the body's with the magnesium-procainamide method [96,97].
oxygen requirements could also be decreased greatly. Bretschneider also developed the idea of buffering of
the cardioplegic solution as an important principle of
myocardial protection [92,94]. This continuing work
Cardioplegia
on cardioplegia in Europe was important to the even-
The first use of "elective cardiac arrest" was by Melrose tual resurgence of interest in America in the 1970s.
in 1955, who also coined the term "cardioplegia" for
the technique [77]. Melrose used a solution con-
Reassessment of myocardial
taining potassium to remove the transmembrane
damage
electrical potential and hence to stop the cardiac im-
pulse and arrest the heart in diastole. However, once In the 1960s surgeons reviewing the complications
again, the paper by Melrose makes it clear that his of cardiac surgery did not consider that the complica-
initial impetus to devise the technique was to reduce tions were due to the surgery itself. Slowly data accu-
the foaming that occurred with the cardiopulmonary mulated that questioned this prevailing concept. In
machines he was using, in order to reduce air emboli, 1967, Taber's group reported that there was myocar-
and not to protect the heart. dial necrosis following cardiac surgery [98]. He found
Also, during the 1950s there was the first use of that patchy necrosis affected as much as 30% of the
alternate routes of cardioplegia administration and myocardium. In a paper by Najafi's group, the authors
various temperatures [78-80]. Gott et al. used retro- found that there was subendocardial necrosis seen in
grade perfusion of the heart via the coronary sinus patients who underwent valve surgery, with normal
using warm blood with Melrose solution, both experi- coronary arteries [99]. In the setting of double valve
mentally and clinically [78,79]. Lillehei's group also operations Cooley et al. first described the condition
used retrograde perfusion of the coronary sinus with of "stone heart" [100]. This was seen when the
blood during aortic valve surgery [80]. ischemic time was prolonged, and the hearts went
Gradually as experience with the technique increased into a state of ischemic contracture.
[81], the long-term effects of Melrose solution became Other investigators also found that patients under-
known. Surgeons found that there was late vascular going valve surgery, who had otherwise normal coron-
and myocardial injury in these patients [82-88]. As a ary arteries, had perioperative myocardial infarction
result, surgeons abandoned the technique. [101,102]. Storstein et al. studied the mechanisms
Some surgeons used direct ostial cannulation of the of these infarctions [103]. In other studies, patients
coronary ostia in order to perfuse the heart during undergoing atrial septal defect repair had enzyme
surgery. However, reports of ostial stenoses discour- evidence of myocardial infarction [104]. This gradu-
aged most surgeons from using this technique [89,90]. ally led surgeons to once again question whether the
In the late 1950s and early 1960s Shumway intraoperative myocardial protection was effectively
and Lower reported their work using hypothermic protecting the heart, and whether they could improve
methods to protect the heart [91]. The use of their techniques.
hypothermia became widespread, and combined with
intermittent ischemia became the dominant method Reintroduction of cardioplegia
of myocardial management during cardiac surgery in Some investigators, such as Tyers, identified the
the USA during the 1960s. Despite the problems with problems with Melrose solution as toxicity due to
Melrose solution, some surgeons in Europe continued inappropriately high ionic concentrations, rather than
to use and develop cardioplegia [92]. Bretschneider due to the idea of electromechanical arrest in and
and others continued to develop the methods of car- of itself [105,106]. In 1973 Gay and Ebert pioneered
dioplegia based on an "intracellular" electrolyte solu- the reintroduction of cardioplegia using crystalloid
tion, which reduced transmembrane gradients, and solutions with much lower concentrations of KC1,
arrested the heart [93-95]. Others, such as Hoelscher, which were just sufficient to give electromechanical
studied the effects of magnesium-procainamide arrest [107]. In 1974 Hearse's group reported their
as compared to potassium citrate cardioplegia, and experimental work with a potassium chloride solution

17. CHAPTER 1
[108]. In 1976 another paper extended this work cardioplegia, the so-called terminal "hot-shot," was
[109]. These experimental papers led to the develop- confirmed experimentally [128] and clinically [129] to
ment of cardioplegic solutions for clinical use, such as be advantageous to myocardial metabolism.
the St Thomas' solution [108-112], which was first Buckberg's group also investigated the use of amino
used clinically in 1976 [ 110]. acids in the cardioplegia to provide substrates for
A great deal of work ensued on the various com- Kreb's cycle [ 130]. This method of substrate enhance-
ponents of cardioplegia solutions, on what should be ment has been shown to be beneficial clinically, reduc-
included in the solutions, and in what concentrations. ing the need for inotropic support or the use of the
Many papers were written on the proper use and con- intraaortic balloon pump [131-133]. This work also
centrations of buffers, Mg2+, Ca2+, acid-base balance, led to the development of "secondary" blood cardio-
local anesthetics, and even oxygen. plegia to resuscitate poorly functioning injured hearts
Some investigators wanted to deliver oxygen during at the end of the operation with a further period of
the arrest period and introduced oxygen into the car- warm cardioplegic arrest [ 134,135].
dioplegia solutions to "oxygenate" them [113,114].
There was even interest in the use of artificial solutions
Continuous cardioplegia
such as fluorocarbons for cardioplegia because of their
oxygen-carrying capacity [115-118]. Salerno's group at the University of Toronto was
interested in myocardial protection, both experiment-
ally and clinically. They questioned whether surgeons
Blood cardioplegia
could avoid ischemia altogether [136]. Several investi-
The interest in delivering oxygen and buffering the gators had used continuous cold blood cardioplegia,
cardioplegia solution led investigators to question in patients undergoing valve surgery [137], in acute
whether the best buffer and oxygen-carrying could be postinfarction mitral regurgitation [138], and in
achieved by blood itself. Dr Gerald Buckberg's group patients with ventricular hypertrophy [139].
working at UCLA did a large amount of experimental The use of continuous blood cardioplegia was done
work that led to the development of blood cardio- in an effort to provide oxygen and substrate through-
plegia in the late 1970s [119]. Other surgeons were out the operation. This eventually led to questions
also interested in the technique [120-122], its use about the ability to deliver oxygen at lower tempera-
spread, and it became widely adopted as a cardioplegic tures. It was well known that the oxygen-hemoglobin
method during the 1980s. dissociation curve was shifted to the right by hypo-
Nevertheless, there are many proponents of thermia, and interfered with unloading of oxygen at
crystalloid cardioplegia [113,114,123], and other the cellular level. The question was "Did we need
methods of myocardial protection such as fibrillatory hypothermia"? If we used a warm induction dose of
arrest [124,125], who continue to use their methods cardioplegia, cold in the middle, and a "hot-shot" at
with good results. the end, did we really need the cold in the middle? Ali
Dr Buckberg's group continued to work on has summarized the theoretical background and
myocardial protection and developed several very rationale of the technique [ 140,141 ].
important techniques. Their work asked whether we After Salerno reintroduced the use of continu-
could use cardioplegia not merely to prevent damage, ous normothermic blood cardioplegia [142], initial
but also to act as a form of treatment, and to reverse experimental [143] and clinical [144-146] work led to
injury to the myocardium. renewed interest in the technique. It led to the devel-
They reported the use of warm blood cardioplegia opment of new technology in order to use the tech-
given to induce cardiac arrest and replenish high- nique to advantage. Visualization could be difficult, so
energy phosphates in energy-depleted hearts before a variety of "blowers" were developed to aid the sur-
giving cold cardioplegia [126]. This is important in geon [147,148]. Some investigators developed the use
chronically ill patients, and also those suffering from of equipment to monitor the adequacy of perfusion
acute ischemia [127]. during the operation. Other groups explored the
This led to investigations altering the conditions physiological limits of the technique. Could the flow
of reperfusion (pressure, temperature, etc.) at the be interrupted, and if so, for how long? This was stud-
end of the arrest period. The use of terminal warm ied experimentally [149,150] and clinically [151-154].

18. History of myocardial protection
There was initially some concern about the issue performed from the aorta to the coronary sinus. This
of neurologic protection [155]. However, other in- was modified by the ligation of the coronary sinus
vestigators found that the neurologic threat was not to facilitate retroperfusion of the myocardium (the
seen in their studies [156-160]. A great deal of work Beck II operation). By 1954 Beck had performed the
ensued concerning the use of normothermic tech- operation on 43 patients and symptoms of angina
niques. This was summarized in a monograph [5]. were improved in 88% [176]. However, it was a
After the initial flush of enthusiasm, the technique has difficult operation to perform using the technology
found its niche, and shown that myocardial protection then available. The difficulty of the operation, early
can be achieved with methods other than hypother- surgical failures, and deaths led to the abandonment
mia, which had become so deeply entrenched. of the procedure.
In 1956 the pioneering work in cardiac surgery
from the University of Minnesota extended to the
Retrograde cardioplegia
investigation of cardiac perfusion and cardioplegia.
There was a resurgence of interest in coronary sinus Gott and Lillehei first used retrograde continuous
retroperfusion of the heart in the early 1980s, led by normothermic blood cardioplegia in a dog model
Gundry, Chitwood, Menasche, Fabiani, Carpentier, [78] using potassium citrate blood cardioplegia as
Fuentes, and Chiu, among others. Coronary sinus per- described by Melrose. They also went on to use the
fusion was used initially with crystalloid cardioplegia, technique clinically in valve surgery [79,80]. However,
and then with blood cardioplegia, and both were used as outlined above, other technical developments
"cold." However, the need to deliver cardioplegia in superceded this technique.
a near continuous fashion for the normothermic Work continued on retroperfusion in experimental
techniques of warm heart surgery led some surgeons models. In 1967 Hammond et al. found that retro-
to reexamine the retrograde route of administration perfusion provided some myocardial protection dur-
[161,162]. It had been used by surgeons sporadic- ing coronary artery ligation in dogs [177]. In 1973
ally over the years [163—169], but became much more Lolley et al. found that retroperfusion with substrate
wide-spread after the upsurge in interest in normo- enhancement gave better protection during nor-
thermic techniques. mothermic ischemic arrest [178]. The technique of
Thebesius first described the anatomy of the coro- retroperfusion of the heart was picked up again clinic-
nary veins in 1708 [170], and this was studied further ally in the following decade.
by Abernathy in 1798 and Langer in 1880. This led to There were several studies done to assess the
the work by Pratt in 1898, in which the feline heart adequacy of retrograde coronary sinus perfusion for
was supported with retrograde perfusion alone for protection of the heart, and it was especially important
up to 1 h [23]. In 1928 Wearn showed that coronary with the normothermic blood cardioplegia technique
veins communicate with thebesian veins [24-26], and because of the question of right ventricle protection
in 1929 Grant found that effluent drained into both [163,179-182]. Most surgeons today have had some
ventricles. Katz showed great variability in venous experience with the retrograde route of cardioplegia
anatomy in 1938 [38]. In the same year, Gregg showed administration, and many would advocate its use
that there was increased backflow through the coron- in redo surgery or valvular surgery. Some surgeons,
ary arteries when the coronary sinus was ligated [27]. such as Buckberg and Salerno, have also advocated the
In 1943 Roberts performed dye injection of the coron- use of simultaneous antegrade and retrograde delivery
ary sinus, and found filling of the coronary arteries of cardioplegia to better perfuse all capillary beds
[171,172]. This suggested that the heart could be [181,183-185].
nourished via retrograde perfusion, and maybe useful
in the treatment of myocardial ischemia.
Other subgroups of patients
Dr Claude Beck tested these hypotheses in 1945.
Beck was an early proponent of coronary sinus inter- The growth of cardiac surgery led investigators to try
vention [48,52-55,173-175]. He found a decrease to improve myocardial protection in various sub-
in the size of an experimental myocardial infarction groups of patients. In particular, some subgroups
with ligation of the coronary veins to that area. This have a higher mortality rate, such as patients at the
led to the "Beck operation," in which a bypass was extremes of age, both the very young and the very old.

19. CHAPTER 1
There has been research in optimizing the methods of pleted. The history of this topic was written, and con-
myocardial protection in these more extreme groups. tinues to be written, by the contributors to this book.
Patients undergoing the repair of congenital heart
defects often have multiple abnormalities, not just
cardiac ones. In addition, there is some evidence that References
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370-447.
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oftheheart./P/iyszo/Lond 1883; 4:29-42.
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14 Ringer S. A third contribution regarding the influence
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This is certainly a promising area for research, both
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20. History of myocardial protection
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21. CHAPTER 1
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