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Chronic Total
Occlusions
A Guide to Recanalization
Third Edition

- V2
^Edited by
Ron Waksman Shigeru Saito

WILEY Blackwell
Chronic Total Occlusions
Chronic Total
Occlusions
A Guide to
Recanalization
T h i rd E d i t i o n

edited by

Ron Waksman
Section of Interventional Cardiology
MedStar Washington Hospital Center
Washington, DC, USA

Shigeru Saito
Heart Center, Cardiology & Catheterization Laboratories
Shonan Kamakura General Hospital
Kamakura City, Japan
This third edition first published 2024
© 2024 John Wiley & Sons Ltd
Edition History
1e, 2006; 2e, 2011 by John Wiley & Sons Ltd
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Library of Congress Cataloging-in-Publication Data
Names: Waksman, Ron, 1952 - editor. | Saito, Shigeru, 1950 - editor.
Title: Chronic total occlusions : A Guide to Recanalization / edited by Ron Waksman, MedStar
Washington Hospital Center, Washington, DC, USA, Shigeru Saito, Shonan Kamakura General
Hospital, Kamakura City, Japan.
Description: Third edition. | Hoboken, NJ : Wiley-Blackwell, 2024. | Includes bibliographical
references and index.
Identifiers: LCCN 2023021444 (print) | LCCN 2023021445 (ebook) | ISBN 9781119517276 (hardback) |
ISBN 9781119517221 (pdf) | ISBN 9781119517313 (epub) | ISBN 9781119517337 (ebook)
Subjects: LCSH: Coronary heart disease. | Arterial occlusions.
Classification: LCC RC685.C6 C485 2023 (print) | LCC RC685.C6 (ebook) | DDC 616.1/23--dc23/
eng/20230605
LC record available at https://lccn.loc.gov/2023021444
LC ebook record available at https://lccn.loc.gov/2023021445
Cover Images: © AYImages/Getty Images; Daria Serdtseva/Shutterstock;
anek.soowannaphoom/Shutterstock; Arctic-Images/Getty Images
Cover Design: Wiley
Set in 9/11.5pt Minion by Integra Software Services Pvt. Ltd, Pondicherry, India
 Contents
List of Contributors, vii
Foreword, x
Preface, xii
Part I Pathology, Indications, and Review
of Clinical Trials
1 The Pathobiology of CTO, 3
Gabby Elbaz-Greener & Bradley H. Strauss
2 Pathology of Chronic Total Occlusions:
Implications for Revascularization, 10
Takao Konishi, Ji Eun Park, Diljon S. Chahal &
Aloke V. Finn
3 Indications and Guidelines of PCI for CTO, 19
Ilan Merdler, Gabriel Maluenda & Ron Waksman
Part II Imaging
4 CT Angiography: Application in Chronic Total
Occlusions, 29
Hidehiko Hara, John R. Lesser, Nicholas Burke &
Robert S. Schwartz
5 IVUS-Guided Recanalization of CTO, 35
Etsuo Tsuchikane
6 Optical Coherence Tomography to Guide the
Treatment of Chronic Total Occlusions, 39
Francesca Maria Di Muro, Giulia Nardi, Niccolò
Ciardetti, Selcuk Kucukseymen, Alessio Mattesini
& Carlo Di Mario
Part III Wires Technology
7 New Coronary Guidewire Technology in Chronic
Total Occlusion Percutaneous Coronary
Interventions, 49
Salman Allana & Emmanouil S. Brilakis
8 Tornus Catheter, 64
Hideaki Kaneda
9 Microcatheters: Characteristics and Use, 69
John D. Hung & James C. Spratt
Part IV Wires Technique
10 CTO Wires: Engineering 101 and Principles of
Wire Manipulation, 83
Rahul Kurup & Luiz Fernando Ybarra
11 Use of Two Wires in the Treatment of CTO, 101
Thierry Lefèvre & Thomas Hovasse
12 Parallel-Wire Techniques, 109
Sudhir Rathore & Takahiko Suzuki
13 Transradial Approach for CTO Lesions, 115
Yutaka Tanaka & Shigeru Saito
14 Subintimal Angioplasty in Coronary CTO, 121
Negar Salehi, Philippe Généreux & George D.
Dangas
15 Antegrade Dissection and Re-Entry
Techniques, 129
Anbukarasi Maran, Carson Keck & Matthew
C. Evans
16 3D Wiring Methods in CTO PCI, 135
Atsunori Okamura
17 Antegrade Fenestration and Re-Entry: An
Alternative Approach to Antegrade Dissection
and Re-Entry, 156
Lorenzo Azzalini & Mauro Carlino
18 Retrograde CTO PCI: Step by Step, 166
Michael Megaly & Ashish Pershad
19 Retrograde CTO Intervention via Vein Grafts, 172
Pavan Reddy & Nelson L. Bernardo
v
vi  Contents
20 Tips and Tricks of the CART and Reverse
CART Technique, 177
Arber Kodra, Chad Kliger, Apurva Patel, Craig
Basman, Tak Kwan & Michael Kim
21 Debulking of CTO, 181
Etsuo Tsuchikane
22 Laser Revascularization in Coronary CTO, 186
On Topaz
23 How to Handle Subintimal Dissections, 203
Pratik B. Sandesara & William J. Nicholson
24 CTO: How to Minimize Contrast-Associated
Acute Kidney Injury, 218
Luis Gruberg
25 Mechanical Support for CTO, 232
Khaldoon Alaswad, Asaad Nakhle, Ankur Gupta,
Katherine J. Kunkel & Mir Babar Basir
26 Stent Grafts to Seal Coronary Perforation, 246
Jasleen Tiwana & Kathleen E. Kearney
27 Complications During Retrograde Approach
for CTO, 250
Yutaka Tanaka & Shigeru Saito
Part V Interesting Cases
28 Interesting Cases I–V, 257
Yutaka Tanaka & Shigeru Saito
Index, 263
 List of Contributors

Khaldoon Alaswad, MD, FACC, FSCAI Niccolò Ciardetti, MD

Henry Ford Hospital & Health System, Detroit, MI, USA Structural Interventional Cardiology
Wayne State University, Michigan, USA Department of Clinical and Experimental Medicine
Careggi University Hospital, Italy
Salman Allana, MD George D. Dangas, MD, PhD
Minneapolis Heart Institute and Minneapolis Heart
Mount Sinai Medical Center, New York, NY, USA;
Institute Foundation
Cardiovascular Research Foundation, New York, NY, USA
Minneapolis, MN, USA
Gabby Elbaz-Greener, MD
Lorenzo Azzalini, MD, PhD, MSc Department of Cardiology, Hadassah Medical Center &
Division of Cardiology The Faculty of Medicine, Hebrew University of Jerusalem
Department of Medicine, University of Washington Jerusalem, Israel
Seattle, WA, USA
Matthew C. Evans, MD
Mir Babar Basir, DO, FACC, FSCAI Medical University of South Carolina
Henry Ford Hospital Charleston, SC, USA
Detroit, MI, USA
Aloke V. Finn, MD
Craig Basman, MD CVPath Institute, Gaithersburg, MD, USA;
Department of Cardiology, Lenox Hill Hospital University of Maryland School of Medicine
New York, NY, USA Baltimore, MD, USA

Nelson L. Bernardo, MD Philippe Généreux, MD

Section of Interventional Cardiology
MedStar Washington Hospital Center
Washington, DC, USA
Emmanouil S. Brilakis,
Minneapolis Heart Institute and Minneapolis Heart
Institute Foundation
Minneapolis, MN, USA
Nicholas Burke, MD
Minneapolis Heart Institute and Foundation
Minneapolis, MN, USA
Mauro Carlino, MD, PhD, MSc
Division of Interventional Cardiology
Cardio-Thoracic-Vascular Department
San Raffaele Scientific Institute
Milan, Italy
Cardiovascular Research Foundation
New York, NY, USA
Luis Gruberg, MD, FACC
Mather Hospital
MD, PhD Donald and Barbara Zucker School of Medicine
New York, NY, USA
Ankur Gupta, MD, PhD
Piedmont Heart Institute
Atlanta, GA, USA
Hidehiko Hara, MD
Minneapolis Heart Institute and Foundation
Minneapolis, MN, USA
Thomas Hovasse, MD
Institut Cardiovasculaire Paris Sud (ICPS)
Massy, France

Diljon S. Chahal, MD
John D. Hung, MBChB, PhD, MRCP
Consultant Cardiologist, Liverpool Heart
University of Maryland School of Medicine
and Chest Hospital
Baltimore, MD, USA
Liverpool University Foundation Trust, UK

vii
viii  List of Contributors

Hideaki Kaneda, MD, PhD Anbukarasi Maran, MD

Okinaka Memorial Institute for Medical Research Medical University of South Carolina
Tokyo, Japan Charleston, SC, USA

Kathleen E. Kearney, MD Carlo Di Mario, MD, PhD, FESC, FACC,

University of Washington Medical Center FSCAI, FRCP
Seattle, WA, USA Structural Interventional Cardiology, Department of
Clinical and Experimental Medicine
Carson Keck, MD Careggi University Hospital, Italy
Medical University of South Carolina
Charleston, SC, USA Francesca Maria Di Muro, MD
Structural Interventional Cardiology, Department of
Michael Kim, MD Clinical and Experimental Medicine
Department of Cardiology, Lenox Hill Hospital Careggi University Hospital, Italy
New York, NY, USA
Alessio Mattesini, MD
Chad Kliger, MD Structural Interventional Cardiology, Department of
Lenox Hill Hospital/Northwell Health Clinical and Experimental Medicine, Careggi University
Hofstra School of Medicine, New York, NY, USA Hospital, Italy

Arber Kodra, MD
Department of Cardiology, Lenox Hill Hospital Michael Megaly, MD, MS
New York, NY, USA Willis Knighton Heart Institute, Shreveport, LA, USA

Takao Konishi, MD Ilan Merdler, MD, MHA

CVPath Institute, Gaithersburg, MD, USA MedStar Washington Hospital Center
Washington, DC, USA
Selcuk Kucukseymen, MD
Structural Interventional Cardiology Asaad Nakhle, MD
Department of Clinical and Experimental Medicine Henry Ford Hospital
Careggi University Hospital, Italy Detroit, MI, USA

Katherine J. Kunkel, MD Giulia Nardi, MD

HonorHealth Scottsdale Shea Medical Center Structural Interventional Cardiology
Scottsdale, AZ, USA Department of Clinical and Experimental Medicine
Careggi University Hospital, Florence, Italy
Rahul Kurup, MD, PhD
South West Sydney Local Health District (Campbelltown William J. Nicholson, MD
and Liverpool Hospitals) and Sydney Medical School Emory Heart and Vascular Center, Division of Cardiology
University of Sydney, NSW, Australia Department of Medicine, Emory University School of
Medicine, Atlanta, GA, USA
Tak Kwan, MD
Department of Cardiology, Lenox Hill Hospital Atsunori Okamura, MD
New York, NY, USA Cardiovascular Center, Sakurabashi Watanabe Hospital,
Osaka, Japan
Thierry Lefèvre, MD, FESC, FSCAI
Institut Cardiovasculaire Paris Sud (ICPS) Ji Eun Park, MD
Massy, France University of Maryland School of Medicine
Baltimore, MD, USA

John R. Lesser, MD
Minneapolis Heart Institute and Foundation Apurva Patel, MD
Minneapolis, MN, USA Department of Cardiology, Lenox Hill Hospital
New York, NY, USA

Gabriel Maluenda, MD Ashish Pershad, MD, MS

MedStar Washington Hospital Center Department of Interventional Cardiology
Washington, DC, USA Chandler Regional Medical Center, Gilbert, AZ, USA
 List of Contributors  ix

Sudhir Rathore, MD Bradley H. Strauss, MD, PhD

Frimley Health NHS Foundation Trust Schulich Heart Centre, Sunnybrook Health Sciences Centre
Surrey, UK University of Toronto, Toronto, ON, Canada

Pavan Reddy, MD Takahiko Suzuki, MD

Toyohashi Heart Centre, Toyohashi, Japan
Section of Interventional Cardiology
MedStar Washington Hospital Center
Washington, DC, USA
Yutaka Tanaka, MD, PhD
Shonan Kamakura General Hospital, Kamakura City, Japan

Shigeru Saito, MD, FACC, FSCAI, FJCC Jasleen Tiwana, MD

Heart Center, Cardiology & Catheterization Laboratories University of Washington Medical Center
Shonan Kamakura General Hospital Seattle, WA, USA
Kamakura city, Japan
On Topaz, MD, FACC, FACP, FSCAI
Negar Salehi, MD Professor of Medicine, Duke University School of Medicine
Mount Sinai Medical Center Durham, NC, USA
New York, NY, USA
Etsuo Tsuchikane, MD, PhD
Pratik B. Sandesara, MD Toyohashi Heart Center, Toyohashi, Japan
Emory Heart and Vascular Center, Division of Cardiology
Department of Medicine, Emory University School of Ron Waksman, MD, FACC
Medicine, Atlanta, GA, USA Section of Interventional Cardiology
MedStar Washington Hospital Center
Robert S. Schwartz, MD Washington, DC, USA
Minneapolis Heart Institute and Foundation
Minneapolis, MN, USA Luiz Fernando Ybarra, MD
London Health Sciences Centre, Schulich School of
James C. Spratt, MD, PhD Medicine & Dentistry, Western University, London, ON
Consultant Cardiologist, Professor of Interventional Canada
Cardiology, St George’s University Hospitals NHS
Foundation Trust, London, UK
 Foreword
Welcome to the world of chronic total occlusion
(CTO) intervention, an exciting and rapidly evolving
field within interventional cardiology. This book is
the third edition within the last 14 years of the popular
Chronic Total Occlusions, a testimonial to the advance-
ment in the field and the interest of interventional car-
diologists to win the battle to safely and effectively
treat CTOs. The book continues to serve as a compre-
hensive guide for both novice and experienced practi-
tioners who seek to enhance their understanding and
skills in the management of CTOs.
The presence of CTOs was initially observed dur-
ing coronary angiography procedures in the mid-20th
century. In the early days of percutaneous coronary
intervention (PCI), CTOs were considered challeng-
ing to treat due to technical difficulties and lack of
suitable equipment and often were referred for surgi-
cal revascularization or medical treatment. However,
the interventional cardiologist was not satisfied with
these alternatives to PCI and strongly believed that
successful revascularization of CTOs can relieve
symptoms, improve cardiac function, and potentially
reduce the need for more invasive procedures like
coronary artery bypass grafting (CABG). Others
questioned the utility of reanalyzing CTO percutane-
ously and its impact on mortality and quality of life.
With the lack of definitive data from randomized
clinical trials, the debate was ongoing. But simultane-
ously skilled operators from around the globe, with
industry support, continued to advance the field and
reported several important breakthroughs through
the past three decades. Among these were the devel-
opment of specialized guidewires with improved flex-
ibility and penetration power, which allowed for more
successful attempts at crossing CTOs.
In the 1990s, the retrograde approach was intro-
duced in the US by Kahn and Hartzler, and in Japan by
the co-editor of this book, Dr. Saito. Navigating and
crossing the occlusion via native collaterals and saphe-
nous vein grafts expanded the possibilities for CTO
intervention and improved success rates. Finally, ded-
icated devices and tools were developed specifically
for crossing and treating these challenging lesions.
These devices include CTO-specific guidewires,
x
microcatheters, and specialized balloon catheters, as
well as devices and techniques to seal perforations.
With the advancement of techniques, devices, and
operator experience, the success rates of CTO inter-
ventions have significantly improved and now stand
in the high 90s success rate, with an acceptably low
rate of procedural complications.
A key to the success of the procedure is adequate
training courses – a dedicated CTO program within
the hospital. These programs comprise skilled inter-
ventional cardiologists who have extensive experience
in performing CTO interventions.
CTO interventions often require a multidiscipli-
nary approach involving collaboration among inter-
ventional cardiologists, imaging specialists, and
cardiac surgeons. A team-based approach ensures
comprehensive evaluation, appropriate patient selec-
tion, and optimal treatment strategies for CTO
patients.
To stay updated with the latest advancements and
techniques in CTO interventions, interventional car-
diologists in the USA participate in continuing medi-
cal education activities. These include conferences,
workshops, case discussions, and comprehensive text-
books, which provide opportunities to learn from
experts and share experiences with peers.
It is important to note that the future of CTO inter-
ventions is dynamic and subject to ongoing innova-
tion. These potential developments hold the promise
of further improving patient outcomes, expanding the
eligibility for CTO interventions, and reducing the
complexity and invasiveness of procedures.
Advancements in imaging techniques, such as the
integration of intravascular ultrasound and optical
coherence tomography to enhance lesion visualiza-
tion and guide treatment strategies, add to this bright
future. Furthermore, the development of novel devices
and tools, including bioresorbable scaffolds and drug-
eluting balloons, may further improve outcomes by
promoting vessel healing and reducing restenosis
rates.
Ongoing innovation in this field is expected to
drive these developments. Artificial intelligence (AI)
is poised to play a crucial role in improving CTO

interventions. AI algorithms can aid in lesion assess-
ment, procedural planning, and complication man-
agement, offering real-time decision support and
enhancing procedural precision.
The third edition of this comprehensive CTO inter-
vention guide aims to provide an in-depth exploration
of the principles, techniques, and tools employed in
the field. Leading experts from around the world have
contributed their knowledge and experience to create
a resource encompassing the entire spectrum of CTO
management. From fundamental physiology and
lesion assessment to procedural planning, equipment
selection, and complication management, each chap-
ter delves into key aspects of CTO intervention,
emphasizing evidence-based practice and innovation
within the CTO community.
Our intent is not only to educate and empower
interventional cardiologists but also to foster a culture
of collaboration and innovation within the CTO com-
munity. In this book, you will find invaluable insights
and pearls of wisdom gained from years of clinical
practice and research. Additionally, we highlight the
importance of a multidisciplinary approach, acknowl-
edging the critical role of imaging specialists, nurses,
Foreword  xi
technicians, and other healthcare professionals in
optimizing patient outcomes.
I would like to extend my special thanks to Jason
Wermers for his guidance and assistance in the edito-
rial management process of this book. Dr. Saito and I
extend our deepest gratitude to all the contributors
who generously shared their expertise and experi-
ences, making this book a comprehensive and valua-
ble resource. We hope that it serves as a guide and
source of inspiration for healthcare professionals
worldwide who are dedicated to improving patient
care through the successful management CTOs.
Ron Waksman, MD, FESC,MSCAI, FACC
Professor of Medicine (Cardiology),
Georgetown University
Associate Director, Cardiology
Director, Cardiovascular Research and
Advanced Education
MedStar Heart and Vascular Institute
MedStar Washington Hospital Center
Washington, DC,
USA
 Preface
The first therapeutic PCI was performed by Dr.
Gruentzig in 1981. The basic idea was to widen a sten-
otic lesion in a coronary artery by balloon dilation.
The key concept at this time was to guide the burst-
resistant balloon to the lesion site, preceded by a deli-
cate atraumatic guidewire. The structure of PCI
balloon catheter consists of several small parts, which
is considered both feasible and best in the current
technology at the time.
The complex procedure of PCI is first broken down
into its component and functional parts. Then, the
aggregate of the parts performs the necessary actions
on the stenotic lesion to achieve a good overall result.
This concept of first breaking it down into parts and
then examining the results as an aggregate of parts is
very important. Smaller units of functional parts are
easier to improve and bring new functionality to. PCI
for chronic total occlusions has also become easier
with the use of improved combinations of functional
components.
The first time I personally performed PCI for a
chronic total occlusion was in 1985 or 1986. The
patient was a man in his 50s suffering from exer-
tional angina pectoris due to a chronic totally
occluded lesion in his right coronary artery. I
reported at an academic conference that I had reo-
pened this patient using a Hartzler LPS (ACS) bal-
loon (2.0 mm), and that six months later, the patient
was still good on angiography. To my surprise, one
of the leading PCI operators at the time stood up
and said, “One-vessel occlusion of the right coro-
nary artery does not affect the prognosis in any
way, and unnecessary PCI is unacceptable”. At that
time, Dr. Gerald Dorros (who was active in
Milwaukee at that time), who was invited to the
conference at that time, stood up and said in front
of everyone, “A young doctor is presenting such a
wonderful treatment, and it is unacceptable for a
xii
doctor not to recognize it.” This was the moment
when I embarked on the long road of PCI for
chronic total occlusion. Looking back, the success
of the PCI of the right coronary CTO at that time
was because I could use a Hartzler LPS balloon
catheter. And what I have learnt from this experi-
ences is that, before opening the door for a new
world, there will be many obstacles, and we have to
overcome them.
At that time, PCI for CTO was performed using
only antegradde approach without contralateral dye
injection. However, as the technique was limited to
that, the success rate was slow to improve even with
the evolution of balloons and wires.
This situation was broken in the 1990s with the
introduction of wires with improved torque control
and penetrating power, the importance of contralat-
eral dye injection was emphasized. Although the
introduction of Intravascular ultrasound (IVUS) in
antegrade approach improved the success rate, the
wire was advanced into the false lumen and could not
enter in the true lumen.
In the 2000s, the retrograde approach was started,
and wires and various devices have been developed to
make this approach easier. With the introduction of
the retrograde approach, more complex CTO lesions
were confronted with PCI than ever before. In the
2010s, Complex high-risk indicated percutaneous
coronary interventions (CHIP-PCI) were started. PCI
for CTO has thus evolved significantly due to (1) tech-
nical developments of operators, (2) introduction of
more sophisticated and advanced devices, and (3)
improved patient’s management strategies This book
documents everything of PCI for CTO from the past
to the future.
Shigeru Saito, MD,
Shonan Kamakura General Hospital.
I PA R T I

Pathology,
Indications, and
Review of Clinical
Trials
 1 CHAPTER 1

The Pathobiology of CTO

Gabby Elbaz-Greener1 & Bradley H. Strauss2,*
1
Department of Cardiology, Hadassah Medical Center & The Faculty of Medicine,
Hebrew University of Jerusalem, Jerusalem, Israel
2
Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
* Corresponding author

Introduction “chronic occlusions” in the lower legs [6], (2) Hard

Chronic total occlusions (CTO) are defined by an
occlusion age of 3 months or greater, with angio-
graphic thrombolysis in myocardial infarction (TIMI)
flow grade 0 or 1 [1]. Our current understanding of
CTO development is based on a limited number of
autopsy specimens, imaging studies, and animal CTO
models. CTO constitute the most challenging lesions
in interventional challenge due to the complexity of
the composition and the geometric issues, such as
CTO entry/exit and the overall occlusion length. In
recent years, additional unique features in specific
types of CTO, such as occluded native arteries in
patients with bypass surgery and stent CTO have been
identified. The challenges of CTO PCI have been the
impetus for developing unique interventional equip-
ment and strategies, and innovative biologic manipu-
lations [2, 3].
Human coronary CTO studies
Our current understanding of human coronary
CTO pathology is based on a small number of
autopsy studies. Srivatsa et al. [4, 5] classified angio-
graphic CTOs in 61 patients according to the age of
the occlusions (<1 year vs ≥1 year). The main points
were: (1) Angiographic occlusion did not necessarily
mean histologic occlusion, with 25% of cases demon-
strating antegrade continuity and subtotal occlusion
(90–95% obstructed). Severe, but not completely
obstructive narrowing, may limit contrast reagent
penetration into lesions and thereby overestimate
the difficulty of a successful guidewire crossing.
This was particularly shown in peripheral arterial
fibrocalcific plaques are a common feature in all
CTOs regardless of age, but there is a definite increase
in harder plaques in older CTOs, while softer (mainly
lipid and loose fibrous tissue) plaques are more likely
to be present in CTOs <1 year old, and (3)
Recanalization of the CTO intimal plaques by neo-
vascular channels was commonly observed at all time
periods, particularly around prominent collections
of inflammatory cells (lymphocytes and macro-
phages) [7] (Figures 1.1A, 1.1B; Figures 1.2A, 1.2B).
Katsuragawa et al. [8] examined autopsy specimens
of 10 patients with CTOs, all presumed to be >1 year
old. They reported similar findings, namely loose and
dense fibrous tissue, atheroma, small recanalization
channels, calcification and inflammatory cellular
infiltrates, but no fresh thrombus (Figures 1.1A, 1.1B).
Small recanalization channels, which traversed the
CTO in 4 cases, were correlated with the angiographic
appearance of a tapering entrance into the CTO, a
well-known favorable sign for successful guidewire
crossing [9]. Thus, there is a histologic basis for the
presence of softer tissue components and recanalization
channels with higher angiographic success rates in
guidewire crossing, most frequently evident in CTOs
<1-year duration [5].
Recently, additional histology has been published
for two specific CTO clinical situations: post bypass
and stented coronary lesions.
(1) CTOs in patients with coronary artery bypass
graft:
The Canadian CTO Registry reported that > 50% of
patients with previous bypass surgery undergoing
coronary angiography had a native artery CTO [10].
In fact, the strongest clinical predictor for coronary

Chronic Total Occlusions: A Guide to Recanalization, Third Edition. Edited by Ron Waksman and Shigeru Saito.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
3
4  PA R T I Pathology, Indications, and Review of Clinical Trials
Ca Ca
MV
Necrotic
Figure 1.1A Hematoxylin-eosin stained human coronary
CTO, demonstrating extensive collagen-rich fibrous tissue,
several patches of calcification (Ca), two small microvessels
(MV), and a large necrotic area (necrotic). (Courtesy of Dr.
Jagdish Butany, University Health Network, Toronto, ON,
Canada.)
M
MV
Ca
Ca
MV
Figure 1.1B Elastin-trichrome stained human coronary
CTO, demonstrating fibrous tissue (lighter staining
material inside the lumen), with two distinct areas of
calcification (Ca) and two microvessels (MV). M = media.
(Courtesy of Dr. Jagdish Butany, University Health
Network, Toronto, ON, Canada.)
CTO formation is coronary artery bypass grafting
[11]. Angiographic follow-up at one year post coro-
nary artery bypass grafting demonstrated ≥1 new
native coronary artery CTO in almost half of the
patients. In 7.5% of patients, the native artery and
the graft supplying that territory were both occluded.
In particular, a pre-operative proximal stenosis
>90% identified the highest risk for a subsequent
new CTO. New native artery CTO post bypass had
long-term prognostic significance: 21% of these
cases had died or experienced nonfatal myocardial
infarction or repeated revascularization at a mean of
7.2 years [12].
Sakakura et al. reported on histologic differ-
ences in 95 CTOs in patients with and without
prior coronary artery bypass grafts (CABG) [13].
In this study, short CTO duration was defined by
histology (rather than actual timing), based on
organizing thrombi (fibrin) and proteoglycan-rich
extracellular matrix, particularly in the middle
of the CTO segment (Figure 1.1A). Longer dura-
tion (non-bypassed) CTOs in contrast demon-
strated more complex features: mainly collagen
1 deposition and moderate calcification (Figure
1.1B). CTOs with bypass grafts were characterized
by the heaviest calcification (including the adja-
cent proximal and distal segments) (Figure 1.2C).
Negative remodeling, defined as reduction in the
CTO vessel cross-sectional area relative to the adja-
cent proximal segment, was least in CTO sections
containing organizing thrombus, followed by cal-
cified sections and proteoglycan-rich thrombus
sections, but highest in non-calcified CTO sections
with collagen type I [13]. This predilection for heavy
calcification likely explains the clinical experience of
lowest PCI success rates in CTOs which have been
previously bypassed [14, 15]. Although bypass sur-
gery is well recognized as the superior revasculari-
zation strategy in patients with high SYNTAX score
and multivessel disease, there is also a downside of
iatrogenic CTO formation, ultimately creating the
most technically challenging CTOs for percuta-
neous revascularization, and a pool of no-option,
symptomatic patients.
(2) CTOs in Bare Metal versus Drug Eluting Stents:
In-stent occlusion accounts for approximately 12%
of all coronary occlusion interventions [16, 17]. The
characteristics of chronic stent occlusion (> 3
months post implantation) were described in a
detailed pathological analysis of a series of 56 stent
occlusions (both bare metal stents [BMS] and drug
eluting stent [DES], mainly first generation) [18].
The 5 most common etiologies in order of fre-
quency were (1) acute thrombotic occlusion (>50%
of cases), (2) restenosis (>20%, mainly in BMS
cases), (3) neoatherosclerosis rupture (10%), and
very infrequently, calcified nodules and hypersensi-
tivity reactions. The timing of stent occlusion

relative to stent implantation was 2 years for acute
thrombotic, 4.5 years for restenosis and 7.4 years for
neoatherosclerosis. The contributing factor most fre-
quently identified was a medial tear (60% of cases),
potentially indicative of more aggressive stent siz-
ing. Less frequently, protrusion of a necrotic core,
overlapping stents, bifurcation stenting, and stent
fracture with complete disruption were also recog-
nized. Neoatherosclerosis (foamy macrophages,
necrotic core) was present in 25% of these stent
CTO, but neointimal calcification was rarely pre-
sent, despite a high prevalence of patients with
diabetes and renal failure (Figure 1.2D). These find-
ings highlight a number of differences between de-
novo and stented coronary CTO.
Current paradigm of CTO evolution
The development of CTOs includes several specific
stages with unique histologic characteristics pre-
sent at each stage. The initial acute event leading
to the development of a CTO is in many cases a
ruptured atherosclerotic plaque with bidirectional
thrombus formation [7]. Clinically the arterial
occlusion may develop insidiously with minimal
symptoms or may present as an acute coronary syn-
drome. In patients with minimal or no symptoms,
the timing of the occlusive event cannot be clearly
identified. In fact, the age of approximately 60%
of CTO cases cannot be reliably dated by symp-
toms [10]. In patients with ST segment elevation
myocardial infarction (STEMI) not treated with
reperfusion therapy, an occluded infarct related
artery has been found in 87% of patients within
4 hours, in 65% within 12–24 hours, and in 45%
at 1 month [19, 20]. Up to 30% of patients treated
with thrombolytic therapy alone have a chroni-
cally occluded artery 3–6 months after MI [21]. In
patients treated with percutaneous coronary inter-
vention (PCI) during evolving acute myocardial
infarction (AMI), approximately 6–11% will have
chronic occlusion of an infarct related artery at 6
months, due to either initial treatment failure or
late re-occlusion [22].
Characterization of CTO development in human
studies is problematic since CTOs are often diagnosed
at a very late stage, and data regarding initial stages
in their evolution is lacking. Several animal models,
particularly rabbit and swine, have been developed
to systematically define the development stages of a
CTO [10, 23]. However, these models have certain
characteristics that could potentially limit their rele-
vance to humans, such as non-coronary location, and
C hapter 1 The Pathobiology of CTO 5
the lack of an underlying atherosclerotic substrate or
significant calcification.
Development of CTOs
Acute arterial occlusion due to atherosclerotic
plaque rupture with thrombus formation is likely
a common initiating event, which then triggers an
inflammatory reaction. In a rabbit CTO model,
the freshly formed thrombus contains platelets and
erythrocytes within a fibrin mesh, which is followed
by an invasion of acute inflammatory cells [24].
This early acute inflammatory response (initial
2 weeks) is accompanied by patchy formation of
a proteolycan-enriched extracellular matrix and
myofibroblast infiltration into the thrombotic
occlusion. At the initial part of the intermediate
stage (6 weeks), there is marked negative arterial
remodeling and disruption of the internal elastic
lamina accompanied by intense intraluminal neo-
vascularization and increased CTO ­perfusion. Total
microvessel cross-sectional area increases 2-fold,
along with a nearly 3-fold increase in the size of
individual intraluminal vessels.
However, by 12 weeks, there is a reduction in both
microvessel formation and CTO perfusion, with
further declines at the advanced stage (18–24 weeks).
This progressive decrease in the CTO perfusion coin-
cides with gradual replacement of proteoglycans by
collagen in the extracellular matrix. Human studies
have shown collagen and calcium accumulation char-
acterize the later stages of CTO maturation (Figures
1.1 and 1.2). The density of the fibrocalcific tissue is
highest at the proximal and distal ends of the lesion
compared to the body. Thus, the tissue components
of the CTO evolve over time with remarkable spatial
variability along the length of the CTO. From a
pathobiology standpoint, three specific regions of the
CTO have been proposed:
(1) The proximal fibrous cap is a thickened struc-
ture at the entrance (the proximal end) of the CTO
containing particularly densely packed collagen. It
usually contains types I, III, V, and VI of collagen.
Type IV collagen has also been observed in calcified
tissues [25]. This region represents a distinct physical
barrier to crossing into the CTO.
(2) The distal fibrous cap also contains densely
packed collagen, but is commonly regarded (although
not proven in studies) as a thinner and softer struc-
ture compared to the proximal cap. This has been part
of the rationale for developing the retrograde
approach to cross the CTO.
6  PA R T I Pathology, Indications, and Review of Clinical Trials
(3) The main body of CTO.
As mentioned earlier, human coronary artery autopsy
studies [4, 5, 8] have shown that the lumen of the
CTO in some cases contains organized thrombus.
Recanalization channels were observed in nearly 60%
of lesions. Unlike the preclinical rabbit femoral artery
model, the frequency of lumen recanalization and
sizes of the channels were similar in different CTO
ages. The intimal plaques within the CTO contained
collagen, calcium, elastin, cholesterol clefts, foam
cells, giant cell atherophagocytes, mononuclear cells
(lymphocytes, monocytes), and red blood cells. “Soft”
or cholesterol-laden lesions were more prevalent in
younger CTOs age (< 1 year); the amount of choles-
terol-laden and foam cells declined with advancing
CTO age. Older age CTOs typically contained hard
fibrocalcific lesions (“hard plaque”).
Extensive recanalization of the intimal plaques by
neovascular channels was frequently evident, partic-
ularly within and adjacent to the sites infiltrated by
inflammatory cells (lymphocytes and macrophages). In
some cases, intimal neovascular channels directly com-
municate with adventitial vasa vasorum. Neovascular
channels were also observed in the vascular medial
layer; the extent of medial neovascularization was pro-
portional to the cellular ­inflammation in the intimal
plaque. The adventitia of the vessel is usually exten-
sively revascularized in CTOs of all ages. Again, the
extent of adventitial neovascularization is correlated
to adventitial cellular inflammation. Munce et al. have
shown peripheral artery CTO model in a rabbit that
a large rise in extravascular vessels surrounding the
occluded artery occurred at early time points, which
was followed by a significant increase in intravascular
vessels within the central body of the occlusion [26].
The temporal and geographic pattern of microvessel
formation and the presence of connecting microves-
sels support the thesis that the extravascular vessels
may indeed initiate formation of the intravascular
channels within the center of the occlusion. However,
as the CTO matures beyond 6 weeks, a reduction in
the size and number of central intravascular micro-
channels was demonstrated, suggesting that many of
the vessels in this region become nonfunctional [26].
Intraluminal microvessel formation
(“Recanalization Channels”)
These microvessels generally range in size from 100 to
200 µm, but can be as large as 500 µm [5]. In contrast
to the vasa vasorum which run in radial direction,
these intimal microvessels run within and parallel to
the thrombosed parent vessel [27], and therefore have
particular relevance for crossing of CTOs as a pathway
for guidewire crossing.
Calcification
Calcification, a major predictor of procedure failure
[28–30], seems to be particularly determined
by coronary occlusion duration. In short dura-
tion coronary occlusions (≤3 months), intimal
plaque calcification was present in 54% of coro-
nary occlusions, but reached 100% in CTO of
>5 years duration [5] (Figure 1.2C). In contrast,
insulin-dependent diabetes mellitus was more fre-
quently observed in patients with predominantly
cholesterol laden or mixed CTOs than in those
with fibrocalcific CTOs [5].
Calcification changes range from crystal formation
to tissue that is histomorphologically indistinguish-
able from bone. Calcification is correlated with chronic
kidney disease, diabetes mellitus, and is a consequence
of aging. Our understanding of the balance between
promotion and inhibition of calcification in the CTO
is much more limited.
The process of the CTO calcification is usually sim-
plified into two mechanisms:
(1) Passive process: This requires high concentrations
of tissue calcium and phosphate but is recognized as a
regulated process [31–34]. It was initially considered
that calcium precipitation occurred when apoptotic
cell fragments and cholesterol crystals served as a
crystallization nidus and the calcium and phosphate
concentration approached the salt solubility product
in the presence of a lower concentration of local cal-
cium-chelating molecules. The formation of hydroxy-
apatite crystals in this way is now regarded as a
semi-regulated process, and the high phosphate levels
might induce vascular smooth muscle cells to differ-
entiate into an osteoblastic phenotype resulting in
bone formation.
(2) Active osseous process: This requires recruit-
ment of osteoblasts and osteoclast-like cells into the
atherosclerotic plaque. This process can be triggered
by immunomodulating cytokines, causing local
production of ossification factors such as BMP-2
[34–36], culminating in producing extra osseous
bone tissue inside the media and lumen of CTO.
Similar to skeletal bone, these bone/cartilage-like
structures are subject to resorption by osteoclast-
like cells.

Collagen Calcium Proteoglycan Fibrin
Figure 1.2 CTO pathology variability: longitudinal
arterial section with CTO cross-section.
A. CTO<1 year: Proteoglycan-enriched tissue with
abundant microvessels near center of CTO, surrounded by
recently formed collagen.
B. CTO>1 year: Dense fibrosis tissue, predominantly
collagen, with a few microvessels. Prominent negative
remodeling in the occluded segment relative to adjacent,
non-occluded segment.
C. Calcified CTO: Particularly common in long-standing
CTOs in previous bypassed arteries. Collagen and heavy
calcification are evident throughout, with calcification
Summary
In this chapter we have summarized the key compo-
nents of CTOs and suggested an impact of each on
C hapter 1 The Pathobiology of CTO 7
A. CTO <1 year
B.CTO >1 year
C. Calcified CTO
D. In-stent CTO
Cholesterol Plaque Microvessels
particularly evident in the deeper vessel layers.
Atherosclerotic plaques with necrotic core are present at
the periphery of artery.
D. In-stent CTO: Small rim of proteoglycan-enriched tissue
and microvessels located within the most inner layer of
the CTO. Dense surrounding collagen is main constituent,
both inside and outside stent struts. Cholesterol plaques
also present in deeper vessel layers outside the stent
struts. Fibrin deposits may be present around the stent
struts and occasionally in center of CTO. The medial layer
is compressed by stent struts.
guidewire crossing. Better understanding of the CTO
structure incorporating the imaging techniques with
advances in guidewires and other plaque modifica-
tion strategies may enable significant improvements
8  PA R T I Pathology, Indications, and Review of Clinical Trials
in CTO revascularization. The pathophysiology of
collagen accumulation and calcification in CTO is
now at the frontier of CTO translational to clinical
research. A biologic approach using locally delivered
collagenase to target matrix collagen within CTOs
to enhance guidewire crossing successes with softer
guidewires has encouraging results in initial clinical
trials [2, 3, 37]. These efforts will hopefully contribute
to higher CTO revascularization success rates and a
wider application of percutaneous revascularization
for appropriate cases in the near future.
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PCI-The Total Occlusion Study in Coronary Arteries-5
(TOSCA-5) trial. Catheter Cardiovasc Interv 2022; 99:
1065–1073.
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The Project Gutenberg eBook of A handbook of
systematic botany
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
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Title: A handbook of systematic botany

Author: Eugenius Warming

Contributor: Emil Knoblauch

Translator: Michael Cresse Potter

Release date: July 21, 2022 [eBook #68580]

Language: English

Original publication: United Kingdom: Swan Sonnenschein, 1895

Credits: Peter Becker, Karin Spence and the Online Distributed

Proofreading Team at https://www.pgdp.net (This file was
produced from images generously made available by The
Internet Archive)

*** START OF THE PROJECT GUTENBERG EBOOK A

HANDBOOK OF SYSTEMATIC BOTANY ***
 A HANDBOOK
OF

SYSTEMATIC BOTANY
BY

DR. E. WARMING
Professor of Botany in the University of Copenhagen
With a Revision of the Fungi by
DR. E. KNOBLAUCH,
Karlsruhe

Translated and Edited by

M. C. POTTER, M.A. F.L.S.
Professor of Botany in the University of Durham
College of Science, Newcastle-upon-Tyne
Author of “An Elementary Text-book of Agricultural Botany”

WITH 610 ILLUSTRATIONS

London
SWAN SONNENSCHEIN & CO
NEW YORK: MACMILLAN & CO
1895

Butler & Tanner,

The Selwood Printing Works,
Frome, and London.
 P R E FA C E .

The present translation of Dr. E. Warming’s Haandbog i den

Systematiske Botanik is taken from the text of the 3rd Danish Edition
(1892), and from Dr. Knoblauch’s German Edition (1890), and the
book has been further enriched by numerous additional notes which
have been kindly sent to me by the author. Dr. Warming’s work has
long been recognised as an original and important contribution to
Systematic Botanical Literature, and I have only to regret that the
pressure of other scientific duties has delayed its presentation to
English readers. Dr. Warming desires me to record his high
appreciation of the careful translation of Dr. Knoblauch, and his
obligation to him for a number of corrections and improvements of
which he has made use in the 3rd Danish Edition. In a few instances
I have made slight additions to the text; these, however, appear as
footnotes, or are enclosed in square brackets.
In the present Edition the Thallophytes have been revised and
rearranged from notes supplied to me by Dr. Knoblauch, to whom I
am indebted for the Classification of the Fungi, according to the
more recent investigations of Brefeld. The Bacteria have been
revised by Dr. Migula, the Florideæ rearranged after Schmitz, and
the Taphrinaceæ after Sadebeck. The main body of the text of the
Algæ and Fungi remains as it was originally written by Dr. Wille and
Dr. Rostrup in the Danish Edition, though in many places
considerable alterations and additions have been made. For the
sake of comparison a tabular key to the Classification adopted in the
Danish Edition is given in the Appendix.
In the Angiosperms I have retained the sequence of orders in the
Danish original, and have not rearranged them according to the
systems more familiar to English students. In any rearrangement
much of the significance of Dr. Warming’s valuable and original
observations would have been lost, and also from a teacher’s point
of view I have found this system of great value. Although at present it
may not be completely satisfactory, yet as an attempt to explain the
mutual relationships, development and retrogression of many of the
orders, it may be considered to have a distinct advantage over the
more artificial systems founded upon Jussieu’s Divisions of
Polypetalæ, Gamopetalæ, and Apetalæ.
With reference to the principles of the systematic arrangement
adopted, I may here insert the following brief communication from
the author (dated March, 1890), which he has requested me to quote
from the preface of Dr. Knoblauch’s edition:—“Each form which, on
comparative morphological considerations, is clearly less simple, or
can be shown to have arisen by reduction or through abortion of
another type having the same fundamental structure, or in which a
further differentiation and division of labour is found, will be regarded
as younger, and as far as possible, and so far as other
considerations will admit, will be reviewed later than the ‘simpler,’
more complete, or richer forms. For instance, to serve as an
illustration: Epigyny and Perigyny are less simple than Hypogny;
the Epigynous Sympetalæ, Choripetalæ, Monocotyledones are,
therefore, treated last, the Hydrocharitaceæ are considered last
under the Helobieæ, etc. Zygomorphy is younger than
Actinomorphy; the Scitamineæ and Gynandræ therefore follow
after the Liliifloræ, the Scrophulariaceæ after the Solanaceæ, Linaria
after Verbascum, etc. Forms with united leaves indicate younger
types than those with free leaves; hence the Sympetalæ come after
the Choripetalæ, the Sileneæ after the Alsineæ, the Malcaceæ after
the Sterculiaceæ and Tiliaceæ, etc.
“Acyclic (spiral-leaved) flowers are older than cyclic (verticillate-
leaved) with a definite number, comparing, of course, only those with
the same fundamental structure. The Veronica-type must be
considered as younger, for example, than Digitalis and Antirrhinum,
these again as younger than Scrophularia; Verbascum, on the
contrary, is the least reduced, and therefore considered as the oldest
form. Similarly the one-seeded, nut-fruited Ranunculaceæ are
considered as a later type (with evident abortion) than the many-
seeded, folicular forms of the Order; the Paronychieæ and
Chenopodiaceæ as reduced forms of the Alsineæ type; and the
occurrence of few seeds in an ovary as generally arising through
reduction of the many-seeded forms. The Cyperaceæ are regarded
as a form derived from the Juncaceæ through reduction, and
associated with this, as is so often the case, there is a complication
of the inflorescence; the Dipsacaceæ are again regarded as a form
proceeding from the Valerianaceæ by a similar reduction, and these
in their turn as an offshoot from the Caprifoliaceæ, etc. Of course
these principles of systematic arrangement could only be applied
very generally; for teaching purposes they have often required
modification.”
In preparing the translation considerable difficulty has been
experienced in finding a satisfactory rendering of several terms
which have no exact equivalent in English. I may here especially
mention the term Vorblatt (Forblad) which I have translated by the
term bracteole, when it clearly applied to the first leaf (or leaves) on
a pedicel; but in discussing questions of general morphology a term
was much needed to include both vegetative and floral shoots, and
for this I have employed the term “Fore-leaf.” Also, the term “Floral-
leaf” has been adopted as an equivalent of “Hochblatt,” and the term
“bract” has been limited to a leaf subtending a flower. I have followed
Dr. E. L. Mark in translating the word “Anlage” by “Fundament.”
At the end of the book will be found a short appendix giving an
outline of some of the earlier systems of Classification, with a more
complete account of that of Hooker and Bentham.
In a book of this character it is almost impossible to avoid some
errors, but it is hoped that these will be comparatively few. In
correcting the proof-sheets I have received invaluable assistance
from Dr. Warming and Dr. Knoblauch, who have kindly read through
every sheet, and to whom I am greatly indebted for many criticisms
and suggestions. I have also to thank Mr. I. H. Burkill for his kind
assistance in looking over the proofs of the Monocotyledons and
Dicotyledons, and Mr. Harold Wager for kindly reading through the
proofs of the Algæ and Fungi. My thanks are also especially due to
Mr. E. L. Danielsen, and I wish to take this opportunity of
acknowledging the very considerable help which I have received
from him in translating from the Original Danish.
 M. C. POTTER.
January, 1895.
 TABLE OF CONTENTS.
BEING THE SYSTEM OF CLASSIFICATION ADOPTED IN THE
PRESENT VOLUME.
(The Algæ and Fungi rearranged in co-operation with Dr. E.
Knoblauch, the other Divisions as in the 3rd Danish Edition.)

PAGE
DIVISION I. THALLOPHYTA 4
A. Sub-Division. Myxomycetes, Slime-Fungi 5
B. Sub-Division. Algæ 8
Class 1. Syngeneticæ 14
„ 2. Dinoflagellata 16
„ 3. Diatomeæ 18
„ 4. Schizophyta 22
Family 1. Schizophyceæ 22
„ 2. Bacteria 26
Class 5. Conjugatæ 41
„ 6. Chlorophyceæ 46
Family 1. Protococcoideæ 47
„ 2. Confervoideæ 53
„ 3. Siphoneæ 59
Class 7. Characeæ 64
„ 8. Phæophyceæ (Olive-Brown Seaweeds) 68
Family 1. Phæosporeæ 68
„ 2. Cyclosporeæ 73
Class 9. Dictyotales 76
„ 10. Rhodophyceæ (Red Seaweeds) 77
Family 1. Bangioideæ 77
„ 2. Florideæ 78
C. Sub-Division. Fungi 84
Class 1. Phycomycetes 96
Sub-Class 1. Zygomycetes 96
„ 2. Oomycetes 100
Family 1. Entomophthorales 102
 „ 2. Chytridiales 102
„ 3. Mycosiphonales 104
Class 2. Mesomycetes 108
Sub-Class 1. Hemiasci 108
„ 2. Hemibasidii 109
Class 3. Mycomycetes (Higher Fungi) 114
Sub-Class 1. Ascomycetes 114
Series 1. Exoasci 116
„ 2. Carpoasci 118
Family 1. Gymnoascales 118
„ 2. Perisporiales 119
„ 3. Pyrenomycetes 125
„ 4. Hysteriales 132
„ 5. Discomycetes 132
„ 6. Helvellales 136
Ascolichenes 136
Sub-Class 2. Basidiomycetes 144
Series 1. Protobasidomycetes 145
„ 2. Autobasidiomycetes 157
Family 1. Dacryomycetes 159
„ 2. Hymenomycetes 159
„ 3. Phalloideæ 172
„ 4. Gasteromycetes 173
Basidiolichenes 176
Fungi Imperfecti 176

DIVISION II. MUSCINEÆ (MOSSES) 181

Class 1. Hepaticæ 188
Family 1. Marchantieæ 190
„ 2. Anthoceroteæ 191
„ 3. Jungermannieæ 191
Class 2. Musci frondosi 192
Family 1. Sphagneæ 193
„ 2. Schizocarpeæ 195
„ 3. Cleistocarpeæ 195
„ 4. Stegocarpeæ 195

DIVISION III. PTERIDOPHYTA 198

Class 1. Filicinæ 205
Sub-Class 1. Filices 205
Family 1. Eusporangiatæ 210
„ 2. Leptosporangiatæ 212
Sub-Class 2. Hydropterideæ 215
Class 2. Equisetinæ (Horsetails) 221
Sub-Class 1. Isosporous Equisetinæ 221
„ 2. Heterosporous Equisetinæ 225
Class 3. Lycopodinæ (Club Mosses) 226
Sub-Class 1. Lycopodieæ 226
„ 2. Selaginelleæ 228
Transition from the Cryptogams to the Phanerogams 234
Asexual Generation of the Cormophytes 234
Sexual Generation; Fertilisation 243

DIVISION IV. GYMNOSPERMÆ 251

Class 1. Cycadeæ (Cycads) 252
„ 2. Coniferæ (Pine-Trees) 255
Family 1. Taxoideæ 259
„ 2. Pinoideæ 262
Class 3. Gneteæ 270
Fossil Gymnosperms 271

DIVISION V. ANGIOSPERMÆ 273

Class 1. Monocotyledones 274
Family 1. Helobieæ 278
„ 2. Glumifloræ 283
„ 3. Spadicifloræ 297
„ 4. Enantioblastæ 308
„ 5. Liliifloræ 309
„ 6. Scitamineæ 323
„ 7. Gynandræ 328
Class 2. Dicotyledones 334
Sub-Class 1. Choripetalæ 337
Family 1. Salicifloræ 337
„ 2. Casuarinifloræ 339
„ 3. Quercifloræ 340
„ 4. Juglandifloræ 349
 „ 5. Urticifloræ 351
„ 6. Polygonifloræ 358
„ 7. Curvembryæ 363
„ 8. Cactifloræ 375
„ 9. Polycarpicæ 377
„ 10. Rhœadinæ 393
„ 11. Cistifloræ 406
„ 12. Gruinales 416
„ 13. Columniferæ 421
„ 14. Tricoccæ 430
„ 15. Terebinthinæ 435
„ 16. Aesculinæ 439
„ 17. Frangulinæ 443
„ 18. Thymelæinæ 448
„ 19. Saxifraginæ 451
„ 20. Rosifloræ 456
„ 21. Leguminosæ 466
„ 22. Passiflorinæ 475
„ 23. Myrtifloræ 482
„ 24. Umbellifloræ 490
„ 25. Hysterophyta 498
Sub-Class 2. Sympetalæ 504
A. Pentacyclicæ 506
Family 26. Bicornes 506
„ 27. Diospyrinæ 510
„ 28. Primulinæ 511
B. Tetracyclicæ 514
Family 29. Tubifloræ 514
„ 30. Personatæ 517
„ 31. Nuculiferæ 531
„ 32. Contortæ 541
„ 33. Rubiales 548
„ 34. Dipsacales 556
„ 35. Campanulinæ 560
„ 36. Aggregatæ 564
Appendix 574
Index 593
 CORRIGENDA.

Page 9, line 12 from top, for Hydrodicton read Hydrodictyon.

„ 14, lines 1 and 2 from top, for as in the preceding case read
in this case.
„ 14, „ 2 and 15 from top, for zygote read oospore.
„ 88, line 15 from bottom, for Periphyses read periphyses.
„ 124, „ 7 „ „ for Chæromyces read Choiromyces.
„ 142, „ 2 „ „ and in Fig. 137, for Bœomyces read
Bæomyces.
„ 152, „ 2 „ top, for Pirus read Pyrus.
„ 152, „ 5 „ „ for Crategus read Cratægus.
„ 216, Fig. 215, for Salvina read Salvinia.
„ 306, line 6 from top, for Pista read Pistia.
„ 316, „ 26 „ „ after Dracæna insert a comma.
„ 337, „ 13 „ „ for end read beginning.
„ 483, „ 11 „ bottom, for Lagerstrœmia read
Lagerstrœmeria.

For ä, ö and ü read æ, œ and ue throughout.

The following are not officinal in the British Pharmacopœia:—page
316, Dracæna (Dragon’s-blood), Smilax glabra; p. 321, “Orris-root”;
p. 326, species of Curcuma, Alpinia officinarum; p. 333, Orchis-
species (“Salep”). On page 296, par. 4, only Pearl Barley is offic. in
the Brit. Phar.
 CLASSIFICATION OF THE VEGETABLE KINGDOM.
The Vegetable Kingdom is arranged in 5 Divisions.
Division I.—Thallophyta, Stemless Plants, or those which are
composed of a “thallus,” i.e. organs of nourishment which are not
differentiated into root (in the sense in which this term is used among
the higher plants), stem, or leaf. Vascular bundles are wanting.
Conjugation and fertilisation in various ways; among most of the
Fungi only vegetative multiplication.
In contradistinction to the Thallophytes all other plants are called “Stem-plants”
(“Cormophyta”), because their shoots are leaf-bearing stems. The name
Thallophyta (Stemless-plants) is to some extent unsuitable, since many of the
higher Algæ are differentiated into stem and leaf.
The Thallophytes are again separated into 3 sub-divisions,
namely:
Sub-Division A.—Myxomycetes, Slime-Fungi, with only 1 class.
Sub-Division B.—Algæ, with 10 classes:
Class 1. Syngeneticæ.
„ 2. Dinoflagellata, Peridinea.
„ 3. Diatomeæ, Diatoms.
„ 4. Schizophyta, Fission Algæ.
„ 5. Conjugatæ.
„ 6. Chlorophyceæ, Green Algæ.
„ 7. Characeæ, Stone-worts.
„ 8. Phæophyceæ, Brown Algæ.
„ 9. Dictyotales.
„ 10. Rhodophyceæ, Red Algæ.
Sub-Division C.—Fungi, with 3 classes:
Class 1. Phycomycetes.
„ 2. Mesomycetes.
„ 3. Mycomycetes, Higher Fungi.

Division II.—Bryophyta or Muscineæ, Mosses. These have leaf-

bearing shoots, but neither true roots nor vascular bundles. The
lowest Mosses have, however, a thallus. Fertilisation is
accomplished by means of self-motile, spirally coiled spermatozoids,
through the agency of water. From the fertilised oosphere a “fruit-
body” (capsule) with unicellular organs of reproduction (spores) is
produced. The spore on germination gives rise to the vegetative
system, which bears the organs of sexual reproduction; and this
system is divided into two stages—the protonema, and the leaf-
bearing plant produced on it.
Alternation of generations:
I. The protonema and the entire nutritive system which bears the organs of
sexual reproduction.
II. The capsule-like sporangium, with spores.
2 Classes: 1. Hepaticæ, Liverworts.
2. Musci, Leafy Mosses.

Division III.—Pteridophyta or Vascular Cryptogams, Fern-like

Plants having leaf-bearing shoots, true roots, and vascular bundles
with tracheides and sieve-tubes. Fertilisation as in the Mosses. From
the fertilised oosphere the leaf-bearing shoot arises, which bears on
its leaves the reproductive organs, the spores, in capsule-like
sporangia. From the germination of the spore a small prothallium is
formed, which bears the sexual reproductive organs.
Alternation of generations:
I. Prothallium with organs of sexual reproduction.
II. Leaf-bearing shoot with capsule-like sporangia.
3 Classes: 1. Filicinæ, True Ferns.
2. Equisetinæ, Horsetails.
3. Lycopodinæ, Club-mosses.

Division IV.—Gymnospermæ. The vegetative organs are in the

main similar to those in the 3rd Division; special shoots are modified
into flowers for the service of reproduction. From the oosphere,
which is fertilised by means of the pollen-tube, the leaf-bearing plant
is derived; this passes the first period of its life as an embryo in the
seed, and continues its development when the germination of the
seed takes place. The organs corresponding to the spores of the two
preceding Divisions, are called respectively the pollen-grain and
embryo-sac. The pollen-grains are multicellular; i.e. they contain an
indistinct prothallium. In the embryo-sac a prothallium, rich in reserve
material (endosperm), with female organs of reproduction, is
developed before fertilisation. The pollen-grains are carried by