Cardiovascular Toxicity and Therapeutic Modalities Targeting Cardio-oncology: From Basic Research to Advanced Study

By Pawan Kumar Maurya

Cardiovascular Toxicity and Therapeutic Modalities Targeting Cardio-Oncology: From Basic Research to Advanced Study analyzes the emerging the field of cardio-oncology, reviewing recent advancements in the field, discussing how to monitor and treat cancer survivors for cardiotoxicity, and identifying potential cardiac side effects in novel cancer therapies. By adopting a translational approach, the book first comprehensively covers the basic science, mechanisms and concepts, which is followed by advanced state-of-art of cardio-oncology. Other sections cover tyrosine kinase inhibitors, Anthracyclines, and biomarkers in cardiotoxicity induced by chemotherapeutic drugs, noninvasive cardiovascular imaging techniques, radiotherapy induced cardiovascular, and more.

Anti-cancer treatment is associated with serious cardiovascular adverse events, including arterial and pulmonary hypertension, supraventricular and ventricular arrhythmias, systolic and diastolic cardiac dysfunction and coronary artery disease. Progress in cancer therapy over the past decades improved long-term survival but increased cancer therapy-related cardiotoxicity. Both traditional chemotherapeutic agents and newer therapies have demonstrated profound cardiovascular toxicities. It is important to understand the mechanisms of these toxicities to establish strategies for the prevention and management of complications—arrhythmias, heart failure, and even death.

• Adopts a translational approach and comprehensively covers the basic science, mechanisms and concepts of cardio-oncology
• Outlines the current knowledge of biomarkers in cancer therapy-related cardiotoxicity
• Provides an understanding of the mechanisms of cardiovascular toxicity of various therapies that may lead to the identification of novel targets to reduce vascular complications

• Language: English
• Publisher: Academic Press
• Release date: May 26, 2022
• ISBN: 9780323904629

Book preview

Preface

In recent years, cardio-oncology has emerged as an important subfield in cardiology aimed at reducing cardiovascular morbidity and mortality in cancer survivors and improving their quality of life. The long-term cancer survival rate has increased significantly with the advent of new, more potent antineoplastic therapies. Recent studies have shown that specific cancer treatments are associated with an increased rate of cardiovascular illness, and in the past 20 years, we have noticed an increase in death from heart failure, ischemic heart disease, arrhythmias, and hypertension among cancer survivors. Specifically, cardio-oncology is concerned with preventing, diagnosing, and treating cardiotoxicity caused by chemotherapy and/or radiotherapy.

Short- and long-term cardiovascular toxicity from anticancer therapy can cause heart failure, as well as exacerbating and/or unraveling preexisting heart disease. Cancer treatment and cardiovascular disease treatment are aimed at improving patients’ quality of life and survival. Radiotherapy, cytotoxic chemotherapy, molecularly targeted inhibitors of the immune system, and antibodies designed to target immune checkpoints are among the current therapies employed to treat advanced cancers. Radiation therapy and chemotherapy, for example, have the potential to negatively impact the cardiovascular system, and significant experience has been gained in both cases. In this book, we have discussed the general aspects related to antineoplastic therapy, including action mechanisms of the most commonly used anticancer agents, cardiotoxic effects of tyrosine kinase inhibitors directed against VEGFR, classification of cardiotoxicity, and mechanisms underlying anthracycline-induced cardiotoxicity. Various anticancer agents are being developed daily, and we have summarized the different varieties of antineoplastic drugs, including traditional, new targeted, and immuno-oncological drugs, as well as their cardiovascular toxicity. There are a number of classic clinical cardiovascular risk factors that are known to predict cardiotoxicity, and along with cardiac biomarkers and imaging techniques, these factors can be used to diagnose cardiotoxicity early on in the subclinical/asymptomatic stage, allowing preventive measures to be taken. Therapeutic advances have also been made in the symptomatic stage, whose outcome is outlined. Several advanced technologies are available for isolating resident cells directly from the heart or for conditioning noncardiac cells to achieve a disease-specific phenotype for optimal outcome. As regenerative principles become more prevalent in clinical practice, rehabilitation providers across the patient continuum will be increasingly involved. Thus, there are numerous opportunities for regenerative rehabilitation as a new multidisciplinary field.

In view of such clinical and healthcare importance of cardiovascular health monitoring, this book has been proposed. The book starts with a brief introduction about the cardiovascular system and the cardiovascular changes associated with aging as a background for consideration of the management of hypertension in an elderly population. Then it focuses on the advances in noninvasive cardiac imaging methods to monitor chemotherapy-induced cardiotoxicity, early detection of impairment of contractile myocardial function, and novel anticancerous drugs related to cardiotoxicity, which are very important for developing onsite clinical applications that can be used in the prevention of diseases.

One of the greatest advantages of this book is the fact that it covers common cardiovascular morbidities, including arrhythmias and heart failure comprehensively. In addition to addressing the fundamental biology and pathophysiology of cardiotoxicity, the book also provides insight into the emergence of new clinical trials, for example, the development and use of QT/QTc monitoring protocols within the context of the most recent clinical algorithms utilized by practitioners.

After numerous deliberations, we came up with the idea to explore the possibility of developing a book on cardiovascular toxicity to partially (if not completely) fill this void. Finally, we decided to develop a book by inviting chapters from experts in the field who have relevant research experience and an understanding of the intricacies of the subject. We had in mind a book that would help to alleviate most of the worries of both students and instructors. We discussed, argued, and disagreed until we came up with the thought that a resource book would be a reasonable format, as it could provide sufficient information and literature for instructors to teach the subject, while providing students with ample information to gain better insight about the subject. Once we formulated these thoughts to develop a resource book, the ball started rolling, and we identified various experts and convinced them to contribute chapters.

This is our maiden effort to produce a book that will serve as a major reference for students and cardiologists involved in general cardiovascular practice, therapeutic modalities targeting cardio-oncology, or advanced cardiovascular imaging. This book will also be of value for clinical oncologists and mid-level providers taking care of patients with various cancers. We hope that we will get support from the readers of this book. We are open to criticism, suggestions, and recommendations that can help to improve the content and presentation of the book. Your suggestions and criticisms will give us an opportunity to explore other aspects of oxidative stress in our future ventures and endeavors.

Chapter 1: Overview of changes in the cardiovascular system

Riya Guptaa; Pawan Kumar Mauryab    a Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India

b Department of Biochemistry, Central University of Haryana, Mahendragarh, India

Abstract

According to cdc.gov, 655,000 Americans die from heart disease every year, i.e., 1 in every 4 deaths in the United States. Heart disease is one of the leading causes of death around the world. In fact, the heart was considered one of the most important organs for the proper functioning of the human body according to ancient Greeks. Since the ancient Greeks, scientists have discovered a lot about the heart, including its physiology and anatomy. Now we know how the blood travels through and from the heart. However, there has never before been a brief description of all the basics of the human heart combined in one review. This review paper tries to achieve just that. It contains all the basics one needs to know about the heart in the shortest and most compact way possible.

Keywords

Heart; Cardiovascular system; Circulatory system

1: Introduction

The cardiovascular system is made up of the heart and the circulatory system [1,2]. The heart works like a pump and transports blood to all the organs, tissues, and cells of the body. The heart beats over 100,000 times a day pumping blood to 60,000 miles of blood vessels [3]. The heart is just like any other tissue and needs a continuous supply of oxygen and nutrient [4]. Heart receives its blood from the coronary arteries, which arise from the aorta roots. The heart consists of three layers: the endocardium (inner layer), the epicardium (middle layer), and the myocardium (outer layer) [5]. The outermost layer is the pericardium, which is the protective membrane of the heart [3]. As blood moves throughout the body, it delivers oxygen and nutrients to the cell and, on the other hand, removes carbon dioxide and waste products accumulated in those cells [4]. Blood moves from the heart to the rest of the body, through the complex networks of arteries, arterioles, and capillaries. Blood is carried back to the heart through venules and veins [6].

The heart is a discrete organ. It consists of four chambers in humans. The right side of the heart has the right atrium and the right ventricle, which receives blood from the periphery and carries it to the lungs via the pulmonary artery. This blood is deoxygenated and is revived in the lungs with oxygen [7]. Once this happens, the re‑oxygenated blood is carried to the left side of the heart. The pulmonary vein takes the blood from the lungs to the left atrium, from where it enters the left ventricle and gets pumped to the aortic arch for distribution to the entire body. [6]

2: Circulatory system

The heart is one of the first organs developed during the embryonic development. [8] It is a powerful pump which circulates blood, nutrients, and oxygen to the entire body. It was considered the most important organ in Greek medicine. Heart disease is one of the leading causes of death around the world, which makes it extremely necessary to understand the genetic, molecular, and environmental basis of the cardiovascular development and diseases [9].

There are two circulatory pathways that arise from the heart.

•The pulmonary circulatory pathway—Is a short loop that starts from the heart, goes to the lungs, and comes back to the heart again.

•The systemic circulatory pathway—This is the pathway that carries blood to parts of the body except the lungs and comes back to the heart again.

2.1: Pulmonary circulation

Pulmonary artery is the main artery coming from the heart. It is a high-flow, low-pressure circuit. The low pressure prevents the fluid from moving out of the pulmonary vessels into the interstitial space and allows the right ventricle to operate at a minimal energy cost [10]. The pulmonary artery divides into two main branches, which brings blood to the lungs from the heart. The blood picks up oxygen and releases carbon dioxide in the lungs. This oxygenated blood then returns to the heart through the pulmonary veins [11].

The oxygen uptake (VO2) and removal of carbon dioxide (VCO2) is increased during exercise increases and reaches to almost 20-fold above the resting values. This increase in gas exchange increases the cardiac output up to sixfold. The sixfold increase in cardiac output increases the convective transport demands of these gases to and from muscles. Thus, exercise causes stress on pulmonary circulation, taking an entire cardiac output while keeping the lungs dry and right ventricles compensated [10].

2.2: Systemic circulation

A functional blood supply is provided to all parts of the body through systemic circulation. Blood returning to the heart picks up oxygen from the lungs, which can then be delivered throughout the body [8]. Systemic circulation also picks up all the waste and carbon dioxide from the body parts and in return provides cells with oxygen and nutrients. The aorta is the main artery leaving the heart with oxygenated blood. The aorta branches off, through arteries and to capillaries to all the tissues and muscles where it delivers oxygenated blood [11]. The deoxygenated blood returns through a system of veins from the tissue capillaries to the right atrium of the heart [12].

The neural control of systemic circulation contains feedback mechanisms, which operate both in short and in long terms through the autonomic nervous system, primarily the sympathetic nervous system. Short-term changes in sympathetic activity are triggered either by reflex mechanisms, which have peripheral receptors, or by a centrally generated response. On the other hand, short-term changes in sympathetic activity are triggered by reflex mechanisms, which involve peripheral receptors or using a centrally generated response. On the other hand, long-term changes are evoked through the modulation of sympathetic nervous system by humoral factors and central mechanisms that involve the hypothalamus [13].

3: Blood vessels

Blood vessels are the channels through which the blood is distributed throughout the body. All the vessels make two closed systems, which start and end at the heart. The pulmonary system takes blood from the right ventricle to the lungs and then brings it back to the left atrium [8]. On the other hand, the systemic system carries blood from the left ventricle of the heart and delivers it to the tissues all around the body, which then eventually returns to the right atrium of the heart. Based on the function and structure, blood vessels can be classified as veins, arteries, or capillaries [14].

3.1: Veins

Veins carry blood to the heart. After passing through the capillaries, the blood enters the smallest of the veins, called venules [15]. From the venules, the blood enters the veins and progressively flows to the larger veins till it reaches the heart. The pulmonary veins in the pulmonary system carry the blood from the lungs to the left atrium of the heart. This blood is highly oxygenated as it is coming out of the lungs. The systemic veins transport deoxygenated blood from the body to the right atrium of the heart. This blood has reduced oxygen due to metabolic activities in the tissue cells [15].

There are three layers in the veins. The innermost layer of the vein is called the tunica intima (or the tunica interna). This layer is made up of simple squamous epithelium, which is surrounded by connective tissue basement membrane with elastic fibers. The middle layer is called the tunica media, and this is primarily made up of smooth muscle [15]. The vessel changes its diameter to regulate the flow of the blood and blood pressure. The outermost layer of the vessel that is attached to the surrounding tissue is the tunica externa or tunica adventitia. This layer contains varying amounts of elastic and collagenous fibers. The connective tissue of this layer is dense and is adjacent to the tunica media, but changes to loose connective tissue near the periphery [16].

In the veins, the smooth muscle and connective tissue layers are thin, which makes the walls thin and thus allows more blood to flow through. This is because the blood in the veins has lower pressure as compared to the arteries in which the walls are thicker. This allows the veins to hold more blood. At any given time, almost 70% of the blood volume is in the veins. Medium and large veins have venous valves. These help keep the blood flow toward the heart. Venous valves are important, especially in the arms and legs, to prevent the backflow of blood against gravity [14].

3.2: Arteries

Arteries carry the blood away from the heart. Pulmonary arteries are responsible for the transport of less oxygenated blood from the right ventricle toward the lungs. On the other hand, systemic arteries transport oxygenated blood from the left ventricle to the tissues. Blood is carried from the vesicles into the large, elastic arteries, which branch into smaller and smaller arteries. The smallest microscopic arteries are called arterioles. Arterioles regulate blood flow into the tissue capillaries. At any given time, 10% of the total blood is in the arterial system. The arteries have the same three walls as the veins. However, the tunica interna and tunica media are thicker in the arteries, and therefore more flexible [14].

Arteries undergo structural changes as they age. Changes include gradual thickening of arterial walls, increase in conduit artery diameter, and changes in wall content (i.e., less elastin, advanced glycation end-products); these changes occur in both the central and peripheral arteries. The effect of this is on artery function as they increase arterial stiffness. Most importantly, arterial function changes directly affect cardiovascular events, which are independent of age and other cardiovascular risk factors. Thus, the measurement of arterial function and health can predict one’s biological and chronological age [17].

3.3: Capillaries

Capillaries are the most abundant and the smallest of the blood vessels. They connect the vessels and carry blood away from the heart (arteries) and return the blood back to the heart (veins). Capillaries perform the function of exchange of materials between the blood and the tissue cells. Distribution of capillaries varies with the body tissues and depends on the metabolic activity of the location [18].

The skeletal muscle, liver, and kidneys have an extensive network of capillaries due to their high metabolic activity and thus require an abundant supply of nutrients and oxygen. In contrast, tissues like the connective tissues have a comparatively less supply of capillaries. Lens, cornea, and the epidermis of skin all completely lack any supply of the capillary network. At any given time, 5% percent of the total blood volume is present in the capillaries. And the other 10% is in the lungs. Smooth muscle cells of the arterioles regulate the transportation of blood flow in the capillaries [14].

4: Heart valves

The heart consists of two types of valves. These help the blood flow in the right direction. The valves present between the atria and the ventricles are known as atrioventricular valves (they are also called the cuspid valves), and the bases of the large vessels that leave the ventricles are known as semilunar valves.

The right atrioventricular valves is called the tricuspid valve, and the left atrioventricular valve is called the bicuspid or mitral valve. The valve present between the right ventricle and the pulmonary trunk is the pulmonary semilunar valve. The valve present between the left ventricle and the aorta is called the aortic semilunar valve. Atrioventricular valves close when the ventricles contract to prevent blood from flowing back into the atria. Semilunar valves prevent the blood from flowing back into the ventricles when they relax [19].

5: Physiology of heart

Heart’s conduction system consists of several components. The first component is the sinoatrial node, which initiates the impulse at the rate of 70 to 80 times per minute [20]. This is called the pacemaker of the heart because it establishes the rhythm of the heartbeat. Other parts of the conduction system include the atrioventricular node, atrioventricular bundle, bundle branches, and conduction myofibers. These components coordinate the relaxation and contraction of the heart chambers [14].

6: Cardiac cycle

The cardiac cycle describes all the events that occur during a single heartbeat. It is a stepwise process of how the heart works, altering from contraction to relaxation of the myocardium walls in the heart chambers, which is coordinated by the conduction system during a single heart beat. Systole is the contraction phase, and diastole is the relaxation phase of the cardiac cycle. In the normal heart rate, one cardiac cycle is 0.8 s. [14] Dr. Carl Wiggers made a detailed diagram of all the specific steps of the cardiac cycle in his publication in 1921. This diagram came to be known as the Wiggers diagram. It is still the most commonly used diagram to teach cardiac cycle today [21]. A paper published by the Wright brothers in 2020 introduced the Wright table, which is a novel tool for teaching and learning the cardiac cycle. This table supplements the 100-yr-old Wiggers diagram, which is usually difficult to learn. The Wright table is a compact representation of the information showing (1) the pressures and flow change over time of each component and (2) the heart working as a pump, filling, and emptying the ventricles [21].

7: Heart sounds

Heart sounds are produced from the blood flowing through the heart chambers and the opening and closing of the heart valves during the cardiac cycle. [20] The vibrations of heart chambers from the blood flow create audible sounds: the more turbulent the blood flow, the stronger the sound due to more vibrations being created. These sounds are known as lub-dub. As the sounds are created from the blood flow, the turbulence of the blood flow can be measured using the same variables that measure the flow of all liquids. These variables include density, viscosity, velocity, and the diameter of the column through which the fluid is traveling [22].

A typical medical examination uses a stethoscope as a cornerstone of physical medical examinations and a valuable first-line tool to evaluate a patient. If the heart sounds are unusual, they are called murmurs [14]. There are other pathological sounds which are very characteristic that have major pathophysiological consequences. These lesions are heard during systole, diastole, or continuously throughout the cardiac cycle [22].

8: Heart rate

Sinoatrial node alone produces a constant heart rhythm [23]. The atrioventricular node regulates the heart rate by increasing or decreasing it as per the bodies need. Changes in the heart rate are mediated by the cardiac center present in the medullar oblongata in the brain. This center contains both sympathetic and parasympathetic components, which adjust the heart rates according to the changing needs of the body. Heart rate can be affected by peripheral factors like emotions, body temperatures, or ion concentrations. These are mediated through the cardiac center [14].

9: Blood

Blood is the main component of the vascular system. Blood consists of 55% fluids (plasma) and 45% solids (cells). The plasma consists mainly of water, nutrients, hormones, proteins, dissolved waste products, and antibodies [23]. Blood and the bone marrow consist of multiple cells of different kinds. These cells provide functions like hemostasis, oxygen transport, immune defense, and phagocytosis, which are independent of each other and provided by their specialized cells. [24]

The three main categories of blood cells are:

Erythrocytes

Erythrocytes are also called red blood cells. These are small, red, disk-shaped cells [25]. Erythrocytes consist of hemoglobin that combines with oxygen in the lungs and is then transported to the cells of the body. Hemoglobin then brings all the carbon dioxide waste back to the lungs. Erythrocytes are formed in the bone marrow [3].

Leukocytes

Leukocytes are white blood cells. They help in fighting bacteria and infections. If a tissue gets damaged or there is an infection, the number of leukocytes in the blood increases. Leukocytes are formed in the small ends of bones. These can be classed as granular leukocytes (eosinophils, neutrophils, and basophils), and there are three types of nongranular (monocytes, T-cell lymphocytes, and B-cell lymphocytes) [3].

Thrombocytes

Thrombocytes are also called platelets, and they aid in the formation of blood clots by releasing various protein substances. Whenever there is an injury, thrombocytes disintegrate and cause a chemical reaction with the proteins of plasma, forming a threadlike structure called fibrin. Fibrin catches other blood cells, which forms clots and prevents further loss of blood and helps in the healing process [3].

10: Effects on the cardiovascular system due to various physical/environmental factors

10.1: Effects due to aging

Aging has been vastly studied over the last half-century; significant advances have also been made in understanding the same. Interventions to reduce aging such as calorie restriction, pharmacological agents, exercise training, and others have all shown significant alterations in the cardiovascular system as well as other parts.

The cardiovascular system goes through structural as well as functional changes through the ages. As people undergo aging, the arterial veins become stiffer, which leads to higher systolic blood pressure and pulse pressure and also leads to a higher risk of systolic hypertension; this predisposes to LV hypertrophy and maintains a normal LVEF. Due to reduced diastolic filling rate, the heart becomes older and more reliant on late diastolic filling from the left atrium. These may lead to myocardial ischemia and heart failures in older individuals. Mutated proteins accumulate over time, which may lead to ATTRwt in the elderly. Other characteristics of advancing age are posture, exercise, and afterload stress due to blunted CV. Recent studies in caloric restriction, antioxidants, and exercise training all show promise of CV aging. Further research in this field will help in reducing incidence of clinical CV diseases that occur in older adults.