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 Research and Business Chronicles: Biotechnology and Medicine Series
Basic Cardiovascular Physiology

From Molecules to Translational Medical Science

Basic Cardiovascular Physiology
From Molecules to Translational Medical Science
Basic Cardiovascular Physiology
Pasquale Pagliaro, Claudia Penna and Raffaella Rastaldo From Molecules to Translational Medical Science

This book focuses on established cardiovascular principles and

highlights some of the progress achieved by recent research in the Pasquale Pagliaro, Claudia Penna and Raffaella Rastaldo
cardiovascular field. The authors report the basic concepts related to
the functioning of the cardiovascular system necessary for medical
students to understand. To foster learning, in each chapter the
fundamental points are highlighted in italics and/or bold. In addition,
we have added boxes that contain some more detailed information
about physiological mechanisms or clinical aspects are analyzed
and described in greater detail. The book describes the structure and
function of the heart and vascular system for the reader to understand
how the cardiovascular system responds in both health and disease.
The book conveys a unified vision of the function of the heart and the
vascular system, explaining the complexity of the system that goes

Pasquale Pagliaro, Claudia Penna and Raffaella Rastaldo

far beyond the integrated connection between preload, afterload
and cardiac contractility. The endothelium covers the internal part of
the whole cardiovascular system; therefore, endothelial physiology
is treated in several chapters. Given the importance of coronary
circulation in cardiac pathophysiology, this special circulation is
described in detail and enriched with the most up-to-date information.
Several paragraphs and boxes on clinical implications are dedicated
to the principles of electrophysiology and the electrocardiogram. A
space is also dedicated to myocardial ischemia/reperfusion injury
and cardioprotective procedures. The book is written in a linear and
simple language without compromising the scientific rigor of the
various topics covered.

River Publishers River River Publishers

Basic Cardiovascular Physiology:
From Molecules to Translational
Medical Science
RIVER PUBLISHERS SERIES IN RESEARCH AND
BUSINESS CHRONICLES: BIOTECHNOLOGY AND MEDICINE

Series Editors:

PAOLO DI NARDO PRANELA RAMESHWAR

University of Rome Tor Vergata, Italy Rutgers University, USA

ALAIN VERTES
London Business School,
UK and NxR Biotechnologies, Switzerland

Editorial Board:

SONIA MELINO ELISABETH ENGEL

University of Rome Tor Vergata, Italy IBEC, Barcelona, Spain

CARLO GUARNIERI VERONIQUE SANTRAN

University of Bologna, Italy ICELTIS Toulouse, France
CHANDRA PERE GASCON
University of Texas, USA University of Barcelona, Spain

BANERJEE DEBABRATA
Rutgers University, USA

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Basic Cardiovascular Physiology:
From Molecules to Translational
Medical Science

Pasquale Pagliaro
University of Turin, Torino, Italy
and
National Institute for Cardiovascular Research (INRC)
Italy

Claudia Penna
University of Turin, Torino, Italy
and
National Institute for Cardiovascular Research (INRC)
Italy

Raffaella Rastaldo
University of Turin, Torino, Italy

River Publishers
Published, sold and distributed by:
River Publishers
Alsbjergvej 10
9260 Gistrup
Denmark

www.riverpublishers.com

ISBN: 978-87-7022-200-6 (Hardback)

978-87-7022-199-3 (Ebook)

©2020 River Publishers

All rights reserved. No part of this publication may be reproduced, stored in

a retrieval system, or transmitted in any form or by any means, mechanical,
photocopying, recording or otherwise, without prior written permission of
the publishers.
 Contents

Preface xiii

Acknowledgments xv

List of Boxes xvii

List of Abbreviations xix

1 Cardiovascular System 1
1.1 Overview of the Cardiovascular System . . . . . . . . . . . 1
1.2 Conditions Necessary for Blood Movements
in the Cardiovascular System . . . . . . . . . . . . . . . . . 4
1.3 The Sections of the Cardiovascular System . . . . . . . . . 9
1.4 The Blood Contenied in the Various Sections
of the Cardiovascular System . . . . . . . . . . . . . . . . 14

2 Structure and Function of the Myocardial Fiber 17

2.1 Myocardial Fiber . . . . . . . . . . . . . . . . . . . . . . . 17
2.2 Myofibrillar or Contractile Proteins . . . . . . . . . . . . . 20
2.3 Regulatory Proteins . . . . . . . . . . . . . . . . . . . . . . 24
2.4 Structural Proteins . . . . . . . . . . . . . . . . . . . . . . 25

3 Cardiac Electrophysiology 27
3.1 Cardiac Electrophysiology: Overview . . . . . . . . . . . . 27
3.2 Genesis of Resting Membrane Potential . . . . . . . . . . . 31
3.3 The Action Potential . . . . . . . . . . . . . . . . . . . . . 35
3.4 After Depolarizations . . . . . . . . . . . . . . . . . . . . . 39

v
vi Contents

4 Functional Tissue of the Heart 41

4.1 The Properties of Functional Tissues of the Heart . . . . . . 41
4.1.1 Automatism or Chronotropism . . . . . . . . . . . 41
4.1.2 Excitability or Bathmotropism . . . . . . . . . . . 45
4.1.3 Conductivity or Dromotropism: Origin and Diffusion
of the Cardiac Impulse . . . . . . . . . . . . . . . . 48
4.1.4 Contractility or Inotropism . . . . . . . . . . . . . 51
4.1.4.1 The cross-bridge muscle contraction
cycle . . . . . . . . . . . . . . . . . . . . 51
4.1.4.2 Isometric and isotonic contraction . . . . 53
4.1.4.3 Isotonic contraction with a suspended
load . . . . . . . . . . . . . . . . . . . . 54
4.1.4.4 Mixed contraction: isometric and isotonic
contraction with a sustained load . . . . . 55
4.1.4.5 Mixed contraction with different preload
and afterloads . . . . . . . . . . . . . . . 55
4.1.4.6 Contractility and the strength of contraction
in the heart . . . . . . . . . . . . . . . . 57
4.2 Cardiac Contractility and Heavy Meromyosin
Isoforms . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4.3 Excitation-Contraction Coupling . . . . . . . . . . . . . . . 61

5 The Cardiac Cycle 65

5.1 The Heart as a Pressure Gradient Generator . . . . . . . . . 65
5.2 The Phases of the Cardiac Cycle . . . . . . . . . . . . . . . 66
5.2.1 The Isovolumic Systole . . . . . . . . . . . . . . . 68
5.2.2 The Ventricular Ejection Phase . . . . . . . . . . . 69
5.2.2.1 The ejection with acceleration . . . . . . 69
5.2.2.2 The ejection with deceleration . . . . . . 69
5.2.3 The Protodiastole . . . . . . . . . . . . . . . . . . 72
5.2.4 The Isovolumic Relaxation Phase . . . . . . . . . . 73
5.2.5 The Rapid Ventricular Filling Phase . . . . . . . . . 74
5.2.6 The Slow Ventricular Filling Phase . . . . . . . . . 74
5.2.7 The Atrial Systole Phase . . . . . . . . . . . . . . . 75
5.3 The Atrial Pressure Curve . . . . . . . . . . . . . . . . . . 76
5.4 The Cycle of the Right Heart . . . . . . . . . . . . . . . . . 76
5.5 Changes in the Heart Rate and Duration of the Phases of the
Cardiac Cycle . . . . . . . . . . . . . . . . . . . . . . . . . 77
5.6 The Hemodynamic Role of Atrial Systole . . . . . . . . . . 80
 Contents vii

5.7 The Aortic Flow Curve . . . . . . . . . . . . . . . . . . . . 82

5.7.1 The Sounds and the Heart Murmurs . . . . . . . . . 84
5.7.2 Auscultation Points . . . . . . . . . . . . . . . . . 87
5.7.3 Murmurs . . . . . . . . . . . . . . . . . . . . . . . 87
5.8 Cardiac Volumes and Ejection Fraction . . . . . . . . . . . 88
5.9 The Ventricular Pressure-Volume Loop . . . . . . . . . . . 90

6 Cardiac Output and the Venous Return to the Heart 95

6.1 The Cardiac Output . . . . . . . . . . . . . . . . . . . . . . 95
6.2 Factors Determining the Venous Return to the Heart . . . . 96
6.3 The Central Venous Pressure . . . . . . . . . . . . . . . . . 100
6.4 The Cardiac Output and the Venous Return . . . . . . . . . 101
6.5 The Cardiac Output in the Compensated and Decompensated
Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . 105
6.5.1 The Valsalva Maneuver . . . . . . . . . . . . . . . 107

7 Regulation of Cardiac Contraction Force 109

7.1 Intrinsic and Extrinsic Regulation of the Heart Contractile
Force . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
7.1.1 Intrinsic Heterometric Regulation of Contractile
Force . . . . . . . . . . . . . . . . . . . . . . . . . 110
7.1.1.1 Mechanisms of the Frank-Starling
law . . . . . . . . . . . . . . . . . . . . 116
7.1.2 Intrinsic Homeometric Regulation of Contractile
Force: Anrep Phenomenon and Bowditch or Scale
Phenomenon . . . . . . . . . . . . . . . . . . . . . 118
7.1.2.1 The phenomenon of Anrep . . . . . . . . 118
7.1.2.2 The Bowditch effect or staircase
phenomenon . . . . . . . . . . . . . . . 119
7.1.3 Extrinsic Nervous and Humoral Regulation . . . . . 120
7.1.3.1 The Nervous Regulation . . . . . . . . . 121
7.1.4 The Humoral Regulation . . . . . . . . . . . . . . 123
7.2 Combined Effect of Heterometric and Homeometric
Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . 124
7.3 The Regulation of Cardiac Contraction Force and Heart
Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
7.4 Heart Efficiency: Effort Required by the Heart
for Ventricular End-Diastolic Volume . . . . . . . . . . . . 130
viii Contents

8 Arterial Pressure 133

8.1 The Device and the Law of Poiseuille . . . . . . . . . . . . 133
8.2 The Mechanical Factors of Arterial Pressure . . . . . . . . . 138
8.2.1 Increased Stroke Volume . . . . . . . . . . . . . . 138
8.2.2 Increase in Heart Rate . . . . . . . . . . . . . . . . 139
8.2.3 Increasing Total Peripheral Resistance . . . . . . . 140
8.3 Measurement of Resistance . . . . . . . . . . . . . . . . . 141
8.4 Parallel Arrangement of District Resistance . . . . . . . . . 142
8.5 The Regulation of Vascular Resistance . . . . . . . . . . . . 144
8.6 The Arterial Windkessel and the Arterial Pressure . . . . . . 146
8.7 The Impedance to Ventricular Ejection . . . . . . . . . . . . 148
8.8 The Velocity of Propagation and the Length of Pressure
Wave . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
8.9 The Oscillations of I, II and III Order of Arterial
Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
8.10 The Mechanisms of Control of Arterial Pressure . . . . . . 154
8.10.1 Short-term Control Mechanisms . . . . . . . . . . . 156
8.10.1.1 Ischemic response of the central nervous
system (CNS) . . . . . . . . . . . . . . . 157
8.10.1.2 Baroreceptor system . . . . . . . . . . . 157
8.10.1.3 Chemoreceptor system . . . . . . . . . . 159
8.10.2 Medium-term Control Mechanisms . . . . . . . . . 160
8.10.2.1 Exchanges of liquid through the capillary
wall . . . . . . . . . . . . . . . . . . . . 160
8.10.2.2 Renin-angiotensin-aldosterone system . . 161
8.10.2.3 Stress-relaxation phenomenon . . . . . . 162
8.10.3 The Long-term Control Mechanisms . . . . . . . . 162
8.10.3.1 Kidney-body fluids system . . . . . . . . 162
8.11 Hemodynamic and Arterial Pressure Modifications in the
Physical Exercise . . . . . . . . . . . . . . . . . . . . . . . 163
8.12 The Measurement of Arterial Pressure in Humans . . . . . . 165
8.13 The Arterial Pulse . . . . . . . . . . . . . . . . . . . . . . 166
8.14 The Venous Pulse . . . . . . . . . . . . . . . . . . . . . . . 168

9 Work and Heart Metabolism 173

9.1 The Work of the Heart . . . . . . . . . . . . . . . . . . . . 173
9.2 Heart Performance . . . . . . . . . . . . . . . . . . . . . . 176
9.3 The Metabolism of the Myocardium . . . . . . . . . . . . . 178
 Contents ix

10 Electrocardiogram 181
10.1 The Definition of Electrocardiogram and Dipole Theory . . 181
10.2 Morphology and the Meaning of Electrocardiographic
Waves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
10.2.1 Electrocardiographic Intervals and Segments . . . . 196
10.3 Electrocardiographic Leads on the Front Plane and the
Electrical Axis of the Heart . . . . . . . . . . . . . . . . . . 199
10.3.1 Leads on the Frontal Plane . . . . . . . . . . . . . 199
10.3.1.1 Bipolar limb leads . . . . . . . . . . . . 199
10.3.1.2 Unipolar limb leads . . . . . . . . . . . . 202
10.3.2 Leads on the Horizontal Plane . . . . . . . . . . . . 207
10.4 Electrocardiographic Aspects of Conduction Disorders and
of the Main Arrhythmias . . . . . . . . . . . . . . . . . . . 209
10.4.1 Conduction Disorders . . . . . . . . . . . . . . . . 209
10.4.1.1 Sino-atrial block . . . . . . . . . . . . . 210
10.4.1.2 Atrio-ventricular blocks . . . . . . . . . 210
10.4.1.3 The bundle-branch block . . . . . . . . . 214
10.4.2 Extrasystoles and Tachyarrhythmias . . . . . . . . 215
10.4.2.1 Extrasystoles . . . . . . . . . . . . . . . 215
10.4.2.2 Tachyarrhythmias . . . . . . . . . . . . . 220

11 Vascular Hemodynamics 237

11.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . 237
11.2 The Total Energy of Fluids . . . . . . . . . . . . . . . . . . 237
11.2.1 The Lateral, Head and Tail Pressures . . . . . . . . 239
11.3 The Blood Viscosity . . . . . . . . . . . . . . . . . . . . . 241
11.4 The Laminar Flow and the Turbulent Flow . . . . . . . . . 244
11.5 The Visco-Elastic and Contractile Features of Vessels . . . . 247
11.6 The Miogenic Regulation of the Radius of Resistance
Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
11.7 The Flow of the Blood According to the Waterfall
Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
11.8 The Wave of Flow Along the Arterial Tree . . . . . . . . . 255
11.9 The Microcirculation . . . . . . . . . . . . . . . . . . . . . 256

12 Nervous Control of the Cardiovascular System 261

12.1 The Innervation of the Cardiovascular System . . . . . . . . 261
12.2 Action of the Sympathetic and Vagal Nerves on the
Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
x Contents

12.2.1 Action of the Sympathetic Nerves on the Heart . . . 264

12.2.2 Action of the Vagus on the Heart . . . . . . . . . . 266
12.3 Action of the Sympathetic Fibers on the Vessels . . . . . . . 267
12.4 The Sympathetic and Parasympathetic Receptors of the
Cardiovascular Apparatus . . . . . . . . . . . . . . . . . . 268
12.4.1 Adrenergic Receptors . . . . . . . . . . . . . . . . 268
12.4.1.1 Alpha-receptors . . . . . . . . . . . . . . 269
12.4.1.2 Beta-receptors . . . . . . . . . . . . . . . 272
12.4.2 Acetylcholine Receptors . . . . . . . . . . . . . . . 275
12.5 The Nervous Control Centers of the Cardiovascular
Apparatus . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
12.6 The Nervous Reflex Control of the Cardiovascular
Apparatus . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
12.6.1 The Baroreceptors . . . . . . . . . . . . . . . . . . 279
12.6.2 The Ventricular Receptors . . . . . . . . . . . . . . 282
12.6.3 Atrial Receptors are of Different Types . . . . . . . 283
12.6.4 Chemoreceptors . . . . . . . . . . . . . . . . . . . 283
12.6.5 The Axonic Reflexes . . . . . . . . . . . . . . . . . 284
12.7 The Control of the Blood Volume and the Bainbridge
Reflex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

13 Humoral Control of the Cardiovascular System 289

13.1 Catecholamines . . . . . . . . . . . . . . . . . . . . . . . . 289
13.2 Endothial Factors . . . . . . . . . . . . . . . . . . . . . . . 291
13.2.1 Nitric Oxide . . . . . . . . . . . . . . . . . . . . . 291
13.2.2 Endothelial Derived Hyperpolarizing Factors . . . . 295
13.2.3 Endothelial Contraction Factors . . . . . . . . . . . 297
13.2.4 Endothelial Dysfunction . . . . . . . . . . . . . . . 299
13.3 Other Humoral Factors That Act on the Cardiovascular
Apparatus . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
13.3.1 Serotonin . . . . . . . . . . . . . . . . . . . . . . . 301
13.3.2 Prostaglandins . . . . . . . . . . . . . . . . . . . . 302
13.3.3 Plasma Kinins . . . . . . . . . . . . . . . . . . . . 302
13.3.4 Histamine . . . . . . . . . . . . . . . . . . . . . . 303
13.3.5 Antidiuretic Hormone . . . . . . . . . . . . . . . . 304
13.3.6 Natriuretic Factors . . . . . . . . . . . . . . . . . . 305
13.3.7 Orexins or Hypocretins . . . . . . . . . . . . . . . 307
13.4 Renin-Angiotensin-Aldosterone System . . . . . . . . . . . 308
13.5 Apeline and the APJ Receptor . . . . . . . . . . . . . . . . 309
 Contents xi

14 District Circulations 313

14.1 Coronary Circulation . . . . . . . . . . . . . . . . . . . . . 313
14.1.1 The Coronary Arteries and the
Microcirculation . . . . . . . . . . . . . . . . . . . 313
14.1.2 The Venous Coronary Circulation . . . . . . . . . . 315
14.1.3 Anastomosis of the Coronary Circulation . . . . . . 316
14.1.4 The Resistance of the Coronary Circulation . . . . . 316
14.1.4.1 The phasic coronary flow and the
compressive resistance . . . . . . . . . . 316
14.1.4.2 Coronary autoregulative resistance . . . . 321
14.1.4.3 Coronary viscous resistance . . . . . . . 323
14.1.5 Metabolic Mechanism . . . . . . . . . . . . . . . . 323
14.1.6 Nervous Mechanisms . . . . . . . . . . . . . . . . 326
14.1.7 Humoral Mechanisms . . . . . . . . . . . . . . . . 329
14.1.8 Endothelial Mechanisms . . . . . . . . . . . . . . . 330
14.1.9 Myogenic Mechanism . . . . . . . . . . . . . . . . 332
14.1.10 Coronary Flow at Rest and Under Stress . . . . . . 332
14.1.11 Reactive Hyperemia . . . . . . . . . . . . . . . . . 334
14.1.12 The Coronary Reserve . . . . . . . . . . . . . . . . 336
14.2 Cerebral Circulation . . . . . . . . . . . . . . . . . . . . . 339
14.2.1 Autoregulation and Metabolic Regulation . . . . . . 340
14.2.2 Nervous Regulation . . . . . . . . . . . . . . . . . 341
14.3 Splanchnic Circulation . . . . . . . . . . . . . . . . . . . . 342
14.3.1 The Splenic Circulation and the Spleen . . . . . . . 343
14.3.2 The Mesenteric Circulation and the Intestinal
Villi . . . . . . . . . . . . . . . . . . . . . . . . . 343
14.3.3 The Hepatic Circulation . . . . . . . . . . . . . . . 345
14.4 Circulation in the Skeletal Muscle . . . . . . . . . . . . . . 347
14.5 Renal Circulation . . . . . . . . . . . . . . . . . . . . . . . 350
14.6 Cutaneous Circulation . . . . . . . . . . . . . . . . . . . . 354

15 Pulmonary Circulation 357

15.1 The Characteristics of Pulmonary Circulation . . . . . . . . 357
15.2 Variations of Volume of the Lung and the Resistance to the
Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . 362
15.3 The Chemical and Nervous Regulation of the Pulmonary
Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . 364
15.4 The Formation of the Pulmonary Edema . . . . . . . . . . . 365
xii Contents

16 Coordinated Cardiovascular Adaptations 367

16.1 Physical Exercise . . . . . . . . . . . . . . . . . . . . . . . 367
16.2 Alerting Response . . . . . . . . . . . . . . . . . . . . . . 371
16.3 Responses to Hemorrhage . . . . . . . . . . . . . . . . . . 372

17 Myocardial Protection Against Ischemia-Reperfusion Injury 377

17.1 Ischemia and Reperfusion Injury . . . . . . . . . . . . . . . 377
17.2 Pre-Conditioning and Post-Conditioning . . . . . . . . . . . 380
17.3 Pharmacological Pre-Conditioning and Post-Conditioning . 387

18 Lymphatic Circulation 389

18.1 Formation of the Linfa . . . . . . . . . . . . . . . . . . . . 389
18.2 Lymphatic Vessels . . . . . . . . . . . . . . . . . . . . . . 390
18.3 Lymphatic Flow . . . . . . . . . . . . . . . . . . . . . . . 392

19 Functional Imaging of the Cardiovascular System:

How to Study Human Physiology In Vivo 395
19.1 Functional Imaging vs Anatomical Imaging . . . . . . . . . 395
19.2 Functional Methods of Analysis . . . . . . . . . . . . . . . 396
19.2.1 Cardiac Catheterization . . . . . . . . . . . . . . . 396
19.2.1.1 Measurement of cardiac output . . . . . . 396
19.2.1.2 Fractional flow reserve (FFR) . . . . . . 397
19.2.1.3 Electrophysiological mapping . . . . . . 398
19.2.1.4 Positron emission tomography (PET) . . 399
19.2.2 Single-Photon Emission Tomography (SPECT) . . . 399
19.2.3 Echocardiography . . . . . . . . . . . . . . . . . . 400
19.2.4 Computerized Axial Tomography (CAT or CT) . . . 400
19.2.5 Cardiovascular Magnetic Resonance . . . . . . . . 401
19.3 Physiological Parameters in Clinical Practice . . . . . . . . 402
19.3.1 Contractile Function . . . . . . . . . . . . . . . . . 402
19.3.2 Myocardial Perfusion . . . . . . . . . . . . . . . . 404
19.3.3 Myocardial Vitality . . . . . . . . . . . . . . . . . 406
19.3.4 Assessment of Blood Flow in Large Vessels and
Cardiac Output . . . . . . . . . . . . . . . . . . . . 407
19.3.5 Myocardial Oxygenation . . . . . . . . . . . . . . 408
19.3.6 Electric Activation . . . . . . . . . . . . . . . . . . 408

About the Authors 411

 Preface

The cardiovascular system is designed to ensure the survival of all cells of

the body. Cardiovascular physiology describes the mechanisms by which
the appropriate amount of nutrients and oxygen is delivered to the organs
in the various conditions during normal life. The cardiovascular system and
blood flow ensure the survival of all cells by maintaining the immediate
chemical environment of each cell in the body (i.e., the interstitial fluid) at
a composition appropriate for that cell’s normal function by removing the
waste and bringing the nutrients from the interstitial space.
In this book, we will first analyze the conditions necessary for the
movement of blood in the cardiovascular system. To better understand the
pump function of the heart, we will consider first the functional tissue of the
heart describing the structure of the myocardial fibers and then the electric
properties of cardiac cells. Cardiac contractility or inotropism is outlined in
the details before considering the cardiac cycle, heart sounds, and murmurs.
The cardiac output and the venous return to the heart are analyzed in the same
chapter to underline that they are two identical concepts. While the former is
“seen” from the heart to the arteries, the latter is “seen” from the veins to the
heart. Intrinsic and extrinsic regulation of contractile force is considered to
explain the adaptation of cardiac output to the needs of the body.
The arterial pressure determinants, regulation, and measurements are
considered in Chapter 8 of this book where the mechanisms of control of
arterial pressure are described in the details. The fundamental aspects of
cardiac work, heart performance, and myocardial metabolism are described.
Details of the genesis and interpretation of the electrocardiogram, as well
as some electrocardiographic aspects of the conduction disturbances of
the main arrhythmias, are reported in this book. Vascular hemodynamics
and the microcirculation are treated easily. To the nervous control of the
cardiovascular system and the main reflexes of cardiovascular is dedicated a
whole chapter. Another chapter is dedicated to the humoral and local control
of the cardiovascular system. These last two chapters allow an overview of
the cardiovascular system and an integrated approach, before going on to

xiii
xiv Preface

analyze in detail the various district circulations. Several district circulations

are described, but particular emphasis is given to the coronary, cerebral
and pulmonary circulations (a separate chapter is dedicated to the latter).
Coordinated cardiovascular adaptations, including physical exercise, alerting
response, and responses to hemorrhage are considered to see the fundamental
mechanisms at the basis of integrated and coordinated adaptations. To
myocardial protection against ischemia-reperfusion injury is dedicated a
chapter as a paradigmatic example of pathophysiological mechanisms in
response to stressing stimuli in healthy and in pathological conditions.
Finally, lymph circulation is considered a parallel system that cross-talks
with the cardiovascular system. The book ends with a chapter dedicated
to the functional imaging of the cardiovascular system to study human
pathophysiology in vivo.
The book is endowed with a rich iconography and various panels
(BOXES) in which, on the one hand, aspects connected with physics
are treated and, on the other hand, aspects strictly connected with
pathophysiology and clinical aspects are considered.
We tried to write the book in a linear and simple language without
compromising the scientific rigor of the various topics covered. We hope to
find the interest of readers and that they can enjoy using this book during
their studies and their working life. We also hope that readers will find what
they are looking for in this book, that they will find the texts, boxes, and
figures clear and that they will be so generous as to let us know where we can
improve this book in the next editions.
 Acknowledgments

We are deeply grateful to our dear Prof Gianni Losano who recently passed
away. We were lucky enough to get to know him and appreciate his
human characteristics and his remarkable knowledge in the physiological
and medical history. Prof Losano introduced the authors of this book into
the fascinating field of cardiovascular physiology. We also want to thank
dr. Amedeo Chiribiri who permitted us to use the material, which served to
write much of the chapter “Functional imaging of the cardiovascular system”.
Finally, we would like to thank the readers who will give us comments and
suggestions to improve future editions of this book.

xv
 List of Boxes

Box 1.1 Wedge Pressure and Pulmonary Edema . . . . . . . 15

Box 5.1 The Ventricular and Aortic Pressures Increase in the
Ejection Phase with Acceleration and Decrease in the
Deceleration Phase . . . . . . . . . . . . . . . . . . 70
Box 5.2 Bowditch Scale Phenomenon . . . . . . . . . . . . 78
Box 5.3 Atrial Systole in the Presence of Arrhythmias . . . . 81
Box 5.4 The Analysis of the Aortic Flow Curve During
Ejection . . . . . . . . . . . . . . . . . . . . . . . . 83
Box 6.1 Laplace’s Law and the Bernoulli’s Theorem Explain
the Varices and Aneurysms . . . . . . . . . . . . . . 98
Box 6.2 The Fainting Royal Guard . . . . . . . . . . . . . . 99
Box 6.3 Heart Failure with Preserved Ejection Fraction and
Heart Failure with Increased Cardiac Output . . . . 106
Box 7.1 The Heart-Lung Preparation of Starling . . . . . . . 110
Box 7.2 Patterson Curves . . . . . . . . . . . . . . . . . . . 114
Box 7.3 Sarcoendoplasmic Reticulum (SR) Calcium Transport
Atpase (SERCA) . . . . . . . . . . . . . . . . . . . 120
Box 8.1 What is Normal Blood Pressure? . . . . . . . . . . . 168
Box 8.2 A Bit of History: From the Discovery of Blood
Pressure to the Discovery of Hypertension . . . . . . 170
Box 9.1 Calculation of Cardiac Work . . . . . . . . . . . . . 176
Box 10.1 The Dipole Theory . . . . . . . . . . . . . . . . . . 183
Box 10.2 Why the “R” is so High? . . . . . . . . . . . . . . . 195
Box 10.3 Corrected QT and Long and short QT syndromes . . 197
Box 10.4 Identification of Electrical Heart Axis: The Isodiphasic
Rule and the Parallelogram Procedure . . . . . . . . 204
Box 10.5 The Override Suppression and the Preautomatic
Pause . . . . . . . . . . . . . . . . . . . . . . . . . 212
Box 10.6 Atrio-Ventricular Dissociation . . . . . . . . . . . . 214
Box 10.7 Why the Postextrasystolic Pause can be Compensatory
or Non-compensatory? . . . . . . . . . . . . . . . . 217

xvii
xviii List of Boxes

Box 10.8 The Defibrillation . . . . . . . . . . . . . . . . . . . 224

Box 10.9 Mechanisms of Arrhythmias . . . . . . . . . . . . . 224
Box 10.10 Acute Myocardial Infarction . . . . . . . . . . . . . 230
Box 10.11 Wolff-Parkinson-White Syndrome . . . . . . . . . . 233
Box 10.12 Electrocardiographic Alterations in Athletes and
Heritable Heart-Muscle Disorder (Brugada Syndrome,
Cpvt and Arvc) . . . . . . . . . . . . . . . . . . . . 234
Box 13.1 Nitric Oxide and Erectile Dysfunction . . . . . . . . 300
Box 13.2 New Aspects of the RAS . . . . . . . . . . . . . . . 311
Box 14.1 Additional Features of Coronary Circulation in
Healthy and Cardiovascular Diseases . . . . . . . . 338
Box 15.1 How to Determine the Different Blood Flow in the
Various Levels of the Lung . . . . . . . . . . . . . . 361
 List of Abbreviations

5-HT 5-hydroxytryptamine or Serotonin

AC adenylyl cyclase
ACE Angiotensin-Converting converting Enzymeenzyme
ACE2 Angiotensin-converting enzyme 2
ACh acetylcholine
ADH antidiuretic hormone or vasopressin
Akt (see PKB)
AMI acute myocardial infarction
Ang I angiotensin I
Ang II angiotensin II
ANP atrial natriuretic peptide
AP action potential
AQP2 aquaporin 2
ARB Angiotensin II receptor blockers
ARNi angiotensin receptor–neprilysin inhibitors
ARVC arrhythmogenic right ventricular cardiomyopathy
aV apparent or relative viscosity
AV atrioventricular
AVN atrioventricular node
a-vO2 artero-venous difference in O2 concentration
b.p.m beats per minute
BH4 tetrahydrobiopterin
Bk bradykinin
BNP brain natriuretic peptide
BOLD blood oxygen level dependent
CAM cellular adhesion molecules
CaMK II Ca2+ /calmodulin-dependent protein kinase II
cAMP (or AMPc) cyclic adenosine monophosphate
CCS cardiac conduction systems
cGMP (or GMPc) cyclic guanosine monophosphate
CICR calcium-induced calcium release

xix
xx List of Abbreviations

CM calmodulin
CMD coronary microvascular dysfunction
CNP type C natriuretic peptide
CNS central nervous system
CO cardiac output
CO2 carbonic dioxide
COMTs catechol-ortho-methyltransferases
COX I cyclooxygenase I
COX II cyclooxygenase II
CPVT Catecholaminergic catecholaminergic polymorphic
ventricular tachycardia
CT computerized axial tomography
CV conduction velocity
CVLM caudal ventrolateral medulla
CVP central venous pressure
DADs Delayed delayed afterdepolarizations
DAG diacyl-glycerol
DHP dihydropyridine channel-receptor (also known as
L-type Ca2+ channel)
DP diastolic pressure
dP/dt derivative of the pressure
EADs Early early afterdepolarizations
Ec kinetic energy
ECG electrocardiogram
EDCF endothelial derived contractile factor
EDHF endothelial derived hyperpolarizing factors
EDRF endothelial derived relaxing factor
EET epoxy-eicosa-trienoic acids
EF ejection fraction
EG excitable gap
EGFR epidermal growth factor receptor
e-NOS endothelial NOS
ERK 1/2 extracellular signal regulated kinase 1/2
ESPVR end-systolic pressure-volume relationship
ESS end-systolic-slope
ET endothelin
FFR fractional flow reserve
fMRI Functional Magnetic Resonance Imaging
GABA γ-aminobutyric acid
 List of Abbreviations xxi

GC guanylyl cyclase
GPCR G-protein-coupled receptors
GTP guanosine-triphosphate
H2 O2 hydrogen peroxide
HF heart failure
HFpEF HF with preserved EF
HMM heavy meromyosin
HR heart rate
HSPs heat shock proteins
Htc hematocrit
ICAM-1 intracellular adhesion molecule-1
IMLC intermediolateral column
i-NOS inducible NOS
IP3 inositol-triphosphate
IPC Ischemic preconditioning
IRI ischemia-reperfusion injury
KACh muscarinic potassium channels
Kd callidin
LDH-H4 lactic dehydrogenase (myocardial isoenzymes H4)
LMM light meromyosin
L-NAME L-N-nitro-arginine-methyl ester
L-NMMA LN-monomethyl-arginine
L-NNA LN-nitro-arginine
LQTS long QT syndrome
LVH left ventricular hypertrophy
MAOs monoamine oxidases
MAP mean arterial pressure
MCFP mean circulator filling pressure (or mean systemic
pressure)
MDP mean diastolic pressure
MEK 1/2 mitogen-activated extracellular regulated kinase 1/2
kinase pathway
MHC myosin heavy chains
MI myocardial infarction
mito-KATP ATP-dependent mitochondrial K+ channels
MLC myosin light chains
MLCK myosin light chain kinase
MLCP myosin light chain phosphatase
MPLA monophosphoryl-lipid A
xxii List of Abbreviations

mPTP mitochondrial permeability transition pores

MSP mean systolic pressure
MVO2 myocardial oxygen consumption
NA (or NE) noradrenaline (or norepinephrine)
NANC non-adrenergic and non-cholinergic
NCX 3Na+ /1Ca2+ exchanger
NEP Neprilysin
NF-κB nuclear factor-kappa B
NHX sodium/hydrogen exchanger
n-NOS neuronal NOS
NO nitrogen monoxide or nitric oxide
NOS nitric oxide synthase
NPR natriuretic peptide receptor
NSAIDs non-steroidal anti-inflammatory drugs
NTS nucleus of the solitary tract
O2 − superoxide anion
ONOO− peroxynitrite
ox-LDL low density oxidized lipoproteins
P38-MAPK P38-mitogen-activated protein kinase
PAH para-aminohippuric acid
PDE phosphodiesterase
PECAM-1 platelet endothelial cell adhesion molecule-1
PET Positron emission tomography
PG Prostaglandin
Pi inorganic phosphorus
PI3K phospho-inositol-3-kinase
PIP2 phospho-inositol-diphosphate
PKA protein-kinase A
PKB protein kinase B (called also Akt)
PKG protein kinase G
PLC phospholipase C
PLN phospholamban
pO2 partial pressure of O2
PP pulse pressure
PRR (pro)renin receptor
QTc corrected QT
RAAS renin-angiotensin-aldosterone system
RAS renin-angiotensin system
RBF renal blood flow
 List of Abbreviations xxiii

RIC remote ischemic conditioning

RISK Reperfusion Injury Salvage Kinases
ROS reactive oxygen species
RP refractory period
RPF renal plasma flow
RVLM rostral ventrolateral medulla
RyR ryanodine channel-receptor
SA senoatrial
SACT sinoatrial conduction time
SAFE survivor activating factor enhancement
SAN senoatrial node
SERCA Sarco-Endoplasmatic Reticulum Calcium pump (or
calcium transport ATPase)
ShR shear rate
SP systolic pressure
SPECT Single photon emission tomography
SQTS short QT syndrome
SR sarcoplasmic reticulum
SRV systolic residual volume
SS shear stress
STAT-3 signal transducer and activator of transcription-3
STEMI ST elevation myocardial infarction
SV stroke volume or systolic ejection
TK tyrosine kinase
Tn Troponin
TNFα tumor necrosis factor α
TPR total peripheral resistance
VCAM-1 vascular cell adhesion molecule-1
VCS ventricular conduction system
VDRV ventricular diastolic return volume
VEDV (or VTDV) ventricular end-diastolic volume (or ventricular tele-
diastolic volume)
VIP vasoactive intestinal peptide
VSM vascular smooth muscle
VTDP ventricular telediastolic pressure
VV ventricular volume
 1
Cardiovascular System

1.1 Overview of the Cardiovascular System

The cardiovascular or cardio-circulatory system consists of the heart and
the vessels (Figure 1.1). The heart consists of two reservoirs, the right and
left atria, and two intermittent pumps, the right ventricle, and left ventricles.
The right atrium receives blood from various tissues through the upper and
lower cava veins, and then blood flows into the right ventricle through the
ostium of the tricuspid valve. The right ventricle pumps the deoxygenated
blood at low pressure (mean pressure ≈ 15 mmHg) into the pulmonary
artery; the passage of blood from the right ventricle to the pulmonary artery
occurs through the pulmonary valve ostium. Then blood flows into vessels
that form the pulmonary or small circulation. This is composed of arteries,
arterioles, and alveolar capillaries in which the blood is oxygenated; then the
blood flows into the venules and veins ending into the four pulmonary veins,
which bring oxygenated blood back to the left atrium. From this reservoir,
the blood passes into the left ventricle through the bicuspid or mitral valve
ostium. Then the left ventricle pumps the oxygenated blood at high pressure
(mean pressure ≈ 95 mmHg) into the aorta; the passage of blood from the
left ventricle to the aorta occurs through the aortic valve ostium, from which
starts the systemic or large circulation, also consisting of arteries, arterioles,
capillaries, venules, and veins. Through the various collateral vessels of the
aorta, the blood perfuses all organs and tissues. The arterial blood flows in
arterioles, capillaries, and venules to be then collected in larger veins that
eventually merge into the two cava veins. In passing through the capillaries of
the general circulation, the blood returns to be venous, i.e., deoxygenated as
it yields a part of the oxygen that carries and is enriched with carbon dioxide
produced by the metabolism of the tissues.
From a functional point of view, the blood that reaches the right atrium
through two large veins (inferior and superior venae cavae) is venous (deoxy-
genated) blood, that is, relatively poor in oxygen and rich in carbon dioxide.

1
2 Cardiovascular System

Figure 1.1 Serial arrangement of systemic and pulmonary circulation. PA: pulmonary
arteries; PV: pulmonary veins; SCA: systemic circulation arteries; SCV: systemic circulation
veins.

As such it passes into the right ventricle and then into the pulmonary artery.
As it passes through the alveolar capillaries, the venous blood becomes arte-
rial (oxygenated) blood, receiving oxygen from the alveolar air and releasing
carbon dioxide. The oxygenated blood then reaches the left atrium, passes
into the left ventricle and is then pumped into the aorta and its branches.
It should be noted that “arteries” carry blood from the ventricles to the
periphery, whether referring to the pulmonary or systemic circulation, while
“veins” are those vessels that carry blood from the periphery to the atria. It is
not surprising, therefore, that the vessel that starts from the right ventricle is
classified as an artery even if it contains “venous”, deoxygenated blood, while
the vessels that carry blood in the left atrium are classified as veins even if
they contain “arterial” oxygenated blood.
The systemic circulation and the pulmonary circulation are placed in
series with each other (Figure 1.1). It follows that all the blood passes through
the left heart and the systemic circulation in the unit of time, should also
pass through the right heart and the pulmonary circulation. It follows that the
amount of blood that the left ventricle pumps in one minute in the aorta should
be equal to the amount of blood that the right ventricle pumps in one minute in
the pulmonary artery. However, due to some anatomical shunts (anastomosis
formed by communication, at precapillary or postcapillary level, between the
neighboring vessels of the pulmonary and bronchial circulation, and some
 1.1 Overview of the Cardiovascular System 3

coronary vessels that drain blood directly in the left side of the heart), the
amount of blood that the left ventricle pumps in one minute in the aorta
is a little greater (a few mL) than that pumped by the right ventricle in the
pulmonary artery. We can say that the blood pumped by a ventricle is exactly
the same amount it receives as a venous return, but we cannot say that the
amount of blood pumped by the left ventricle is the same amount pumped by
the right ventricle.
The term cardiac output (CO) refers to the quantity of blood pumped by
one ventricle during one minute. It should not be confused with the stroke
volume (SV) that is the amount of blood ejected per contraction. Since the
heart beats a certain number of times per minute and the number of beats per
minute (b.p.m.) constitutes the heart rate (HR), it is easy to understand how
the following relationship between CO, SV, and HR exists:
SV × HR = CO
The SV in a resting 70 kg adult subject is about 70 mL. Since the heart
normally beats about 70 times per minute, i.e., its frequency is 70/min (70
b.p.m.), the cardiac output is given by 70 mL × 70/min = 4900 mL/min.
The CO is not fixed, however, and adapts rapidly to the body’s needs. Of
note, both ventricles are involved in these adaptations, so that if CO of one
ventricle increase also CO of the other ventricle inseases after few seconds.
This implies that cardiovascular properties and regulatory systems exist to
support these mechanisms and adaptations, and these are the main topics of
this book.
The cardiovascular system or apparatus is organized in a series of
sections and parallel districts.
Sections are in series: we can say that the right heart, the pulmonary
circulation, the left heart and the systemic circulation can be considered as
sections of the cardiovascular system. Sections are also all arteries, the set
of arterioles, all capillaries, all venules, and the set of veins for the systemic
and the pulmonary circulation. Therefore, the sections are the parts of the
cardiovascular system placed in series with each other. In the unit of time
sections of the pulmonary circulation and sections of the systemic circulation
are crossed by the same amount of blood pumped by the respective ventricles.
Districts are in parallel: the districts are different from the sections (Fig-
ure 1.2). In Figure 1.2 it is possible to observe how from the aorta depart
smaller arteries for the various districts. Vascular districts are constituted by
the circulations of organs, tissues, and systems perfused by arteries departing
4 Cardiovascular System

Figure 1.2 Systemic and pulmonary circulations are in series. The dotted lines highlight the
parallel organization of the districts within the systemic circulation.

from the aorta. Each of these arteries is subdivided into smaller vessels up
to the capillaries, followed by the venules and veins that merge into one
of the cava veins. The set of vessels that perfuse a district forms a district
circle. Figure 1.2 clearly illustrates how the different circulatory districts are
arranged in parallel. Each organ is in parallel with the other, and within an
organ, the ramifications are also in parallel. It is obvious that even in each
district we can find sections (arterioles, capillaries, etc.) belonging to that
specific district and placed between them in series.

1.2 Conditions Necessary for Blood Movements in the

Cardiovascular System
To have blood circulation, the cardiac activity must produce a pressure
gradient within the cardiovascular system by increasing the arterial pressure
and lowering the venous pressure. Let us consider the conditions necessary
to produce this gradient.
The pumping action of the heart can generate blood movements in the car-
diovascular system only if two conditions are present: a) the mean circulator
filling pressure (see below) is greater than the pressure in the ventricles during
diastole, and b) the vessels are distensible so that in systole the pressure can
increase (pressure pulse) and travel along the arterial tree in a finite time (not
instantaneously in the entire system, as would occur if the vessels had rigid,
non-expansible walls, as predicted by Pascal’s law).
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