Cellular, Molecular, and Environmental Contribution in Cardiac Remodeling: From Lab Bench Work to its Clinical Perspective

By Asim K. Duttaroy and Rahul Mallick

Cellular, Molecular and Environmental Contribution in Cardiac Remodeling: From Lab Bench to Clinical Perspective consolidates the most recent research advances on cellular, molecular, biochemical, and heterogeneous factors contributing to the physiological and pathological cardiac remodeling, elucidating their mechanisms of action and the clinical outcomes of cardiac remodeling. It extensively covers the factors determining cardiac remodeling, including cardiomyocyte regeneration, cardiac stem cells and their therapeutic potential, cardiac resident pericytes, the role of natural bioactive compounds in cardiac remodeling, chronic cardiac adaptations to exercise and more.

This book provides basic science researchers and clinical investigators in cardiology with a current and comprehensive resource on molecular mechanisms and contributing factors to cardiac remodeling, and its effects and impacts on heart health. New research areas for the future, aimed at preventing, limiting, and reversing bad remodeling, are also discussed.

• Provides a concise summary of recent developments in cardiac remodeling research, combining novel information and the latest data published in this field
• Discusses not only cellular and molecular factors impacting cardiac remodeling, but also environmental contributions such as lifestyle and exercise
• Identifies areas for future research and potential novel strategies for translating basic research knowledge to applications in patients

• Language: English
• Publisher: Academic Press
• Release date: Apr 16, 2024
• ISBN: 9780323995719

Asim K. Duttaroy

Dr. Asim K. Duttaroy is a professor at the Faculty of Medicine, University of Oslo, Oslo, Norway. His research programs focus on the roles of food components on growth and development, as well as in the prevention of diseases such as diabetes and cardiovascular disease. He is also investigating the roles of the antiplatelet and antihypertensive properties of fruits and vegetables. His discoveries of antithrombotic factors in tomatoes and kiwifruits are patented internationally, and three companies (Provexis Limited in the United Kingdom, IDIA AS in Norway, and Genimen Pharmacon in India) are working to commercialize these discoveries. He has published over 265 original contributions and reviews, 6 books, and several book chapters and editorials, and he is the Editor-in-Chief of the journal Food & Nutrition Research, as well as a guest editor of several journals such as Nutrients and Frontiers in Physiology.

Book preview

Cellular, Molecular, and Environmental Contribution in Cardiac Remodeling

From Lab Bench Work to its Clinical Perspective

Asim K. Duttaroy

Department of Nutrition, Faculty of Medicine, University of Oslo, Oslo, Norway

Rahul Mallick

A.I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland

Table of Contents

Cover image

Title page

Copyright

Preface

Chapter 1. Cardiac remodeling: Impacts on cardiac health and disease

1. Introduction

2. Physiological cardiac remodeling

3. Exercise-induced cardiac remodeling

4. Pregnancy-induced cardiac remodeling

5. Pathological cardiac remodeling

6. Hypertensive left ventricular remodeling

7. Atrophic cardiac remodeling

8. Ventricular remodeling in myocardial infarction

9. Metabolic remodeling of the heart

10. Diagnosis

11. Consequences

12. Congestive heart failure

13. Therapeutic targets

14. Fibrosis

15. Cardiomyocyte hypertrophy

16. Cardiomyocyte death

17. Vascular remodeling

18. Metabolic remodeling

19. Conclusion

Chapter 2. Physiological cardiac modeling: Effects of exercise and other physical activities

1. Introduction

2. Effects of exercise and cardiovascular system

3. Effects of exercise on the cardiac remodeling

4. Effects of exercise on the left and right ventricles

5. Determinants of exercise-induced cardiac remodeling magnitude

6. Cellular and molecular mechanism of mechanisms of EICR

7. Energy metabolism, exercise, and cardiac remodeling

8. Cellular signaling system, exercise, and cardiac remodeling

9. Conclusions

Chapter 3. Prognostic elements of unfavorable cardiac remodeling

1. Introduction

2. Left ventricular ejection fraction

3. Myocardial infarction

4. Ventricular dilatation

5. Wall thickness

6. Biomarkers

7. Hypertrophy

8. Fibrosis

9. Hemodynamic changes

10. Functional impairment

11. Symptom severity

12. Comorbidities

13. Response to treatment

14. Summary

Chapter 4. Neurohormones in cardiac remodeling and function

1. Introduction

2. Neurohormonal activation

3. The adrenergic nervous system in the heart

4. RAAS perturbation

5. RAAS in cardiac remodeling

6. Conclusion

Chapter 5. Cardiokines and cardiac remodeling

1. Introduction

2. The heart as an endocrine organ

3. Cardiokines in cardiac stress

4. Autocrine/paracrine signaling of cardiokines

5. Endocrine activities of cardiokines

6. Cardiokines as cardiac disorders biomarkers

7. Conclusion

Chapter 6. Comparative effects of fatty acid and glucose in cardiac remodeling

1. Introduction

2. Cardiac hypertrophy impacting fatty acids and glucose metabolism

3. Glucose and cardiac remodeling

4. Fats and cardiac remodeling

5. Conclusions

Chapter 7. Vitamins, minerals, and nutraceuticals: Their cardioprotective functions

1. Introduction

2. Cardiac protection by vitamins

3. Minerals and cardiac remodeling

4. Phenolic compounds and cardiac remodeling

5. Conclusions

Chapter 8. Junctional adhesion molecules: Their roles in integrity and functionality of the heart

1. Introduction

2. Interactions and signaling pathways

3. Major functions

4. Role of junctional adhesion molecules in cardiovascular diseases

5. Conclusion and perspective

Chapter 9. Composition and function of ion channels and their effects on cardiac remodeling

1. Introduction

2. Electrocardiogram: Sensitive and specific technique to measure cardiac electrical activity

3. Overview of cardiac action potential

4. Cardiac action potential regulating ion channels and transporters

5. Trafficking machinery of cardiomyocytes

6. Proarrhythmogenic mechanisms

7. Electrical remodeling in disease conditions

8. Conclusion

Chapter 10. Notch signaling molecules: A driver of cardiac function

1. Introduction

2. Notch signaling pathway

3. Notch signaling in the endocardium during cardiac regeneration

4. Hemodynamic alterations stimulate endocardial Notch signaling

5. Notch signaling in the diseased heart

6. Conclusion

Chapter 11. Neuregulin-1: Can it be useful to treat heart failure?

1. Introduction

2. NRG-1β signaling in the heart

3. Cardiac stress adaptive role of NRG-1β

4. Can NRG-1β be considered as the cardiovascular health marker?

5. Therapeutic potential of NRG-1β

6. Conclusion

Chapter 12. Does endoplasmic reticulum stress break the heart?

1. Introduction

2. Endoplasmic reticulum functions and stress

3. Endoplasmic reticulum stress in cardiac pathology

4. ER stress targeting therapy

5. Conclusion

Chapter 13. Role of pattern recognition receptors in cardiac remodeling

1. Introduction

2. Ligands of pattern recognition receptors

3. Signaling pathways of pattern recognition receptors

4. Pattern recognition receptor–related cardiovascular diseases

5. Targeting pattern recognition receptor–related pathways to treat cardiovascular diseases

6. Conclusion

Chapter 14. Myocardial contractile proteins: Role in disease progression and drug discovery

1. Introduction

2. Cardiac α-actin and cardiomyopathy

3. Myosin in the morphogenesis of the heart

4. Regulation of myosin

5. Actin-myosin structural transition in heart diseases

6. Cardiac troponin: Biomarker of cardiac damage

7. Conclusion

Chapter 15. Growth and proliferation of cardiomyocytes: Roles of energy metabolism, cell death, oxidative stress, and metabolites

1. Introduction

2. Microanatomy

3. Development of the heart

4. Cardiomyocyte cell cycle and regeneration potential

5. Cardiomyocyte senescence in adult heart

6. Cross-talk between cardiomyocytes and cardiac resident other cells during cardiac remodeling

7. Clinical perspective

8. Conclusion

Chapter 16. Cardiac endothelial cells and their cross-talks with neighboring cells in cardiac remodeling

1. Introduction

2. Cardiac endothelial cell transcriptome

3. Functional significance of endothelial cells during cardiac remodeling

4. Maintenance of vascular tone

5. Hemostasis

6. Role in neovascularization

7. Act as conditional immune cells

8. Interaction with cardiomyocytes

9. Cross-talk with leukocytes

10. Differentiation into mesenchymal cells

11. Contribute to cardiac fibrosis

12. Recruitment of endothelial progenitor cells

13. Conclusion

Chapter 17. Pathophysiology of cardiac fibroblasts and impacts on the severity of the cardiac disease

1. Cardiac fibroblasts

2. Cardiac-resident fibroblast activation

3. Origins and characterization of cardiac fibroblasts

4. Fibroblast responses to microenvironmental stimuli

5. Prime regulator of extracellular matrix turnover

6. Electrophysiology of cardiac fibroblasts

7. Contribution to cardiac fibrosis

8. Conclusion

Chapter 18. Involvement of cardiac stem cells in cardiac remodeling or myocardial regeneration

1. Introduction

2. Self-renewal cells in the heart

3. Embryological origin of cardiac stem cells

4. Endogenous cardiac stem and progenitor cells

5. The regenerative capacity of cardiac stem and progenitor cells

6. Metabolism of cardiac stem cells

7. Paracrine role of cardiac stem cells following cardiac injury

8. Cross-talk between cardiac stem cells and other cells

9. Clinical prospect

Chapter 19. Cardiac pericytes and cardiac remodeling

1. Introduction

2. Properties of cardiac pericytes

3. Pericyte secretome

4. Contribution to cardiac homeostasis

5. Contribution to the cardiac remodeling process

6. Are cardiac pericytes and cardiac stem cells similar

7. Therapeutic potential of cardiac pericytes

8. Conclusion

Chapter 20. Macrophages in the remodeling of diseased heart

1. Introduction

2. Identification of cardiac macrophages

3. Origin of cardiac macrophages

4. Role of macrophages during cardiac remodeling

5. Mechanism of macrophage polarization

6. Role of macrophages in ventricular arrhythmia

7. Conclusion

Chapter 21. Inflammatory role of neutrophils in cardiac remodeling: Damage versus resolution

1. Introduction

2. Phenotypic heterogeneity of neutrophils

3. Contribution in adaptive immunity

4. Does circadian oscillation affect the neutrophil counts: Prognostic factor of disease outcome?

5. Dual role of neutrophil infiltration kinetics in cardiac remodeling: Damage versus resolution?

6. NETosis

7. Secreted extracellular vesicle–mediated effects in the heart

8. Provoking granulopoiesis during myocardial infarction

9. Production of specialized proresolving mediators

10. Angiogenic properties

11. Sexual dimorphism in postmyocardial infarction inflammatory responses

12. Conclusion

Chapter 22. Extracellular vesicle in cardiac remodeling

1. Introduction

2. Biophysical properties of extracellular vesicles

3. Role of extracellular vesicles in heart disease

4. Extracellular vesicles in cardiovascular therapeutics

5. Engineering the extracellular vesicles

6. Conclusions

Chapter 23. Long noncoding RNAs and miRNAs: Emerging regulatory roles in cardiac disease research

1. Introduction

2. Functions of long noncoding RNAs

3. Long noncoding RNAs in cardiovascular diseases

4. microRNAs: Potential therapeutic targets for cardiovascular disease

5. Conclusion

Index

Copyright

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Preface

Welcome to Cellular, Molecular, and Environmental Contribution in Cardiac Remodeling, a comprehensive exploration into the intricate web of factors influencing the dynamic process of cardiac remodeling. This book delves into the cellular and molecular intricacies that underlie the transformations in the heart’s structure and function, focusing on the impact of various environmental elements.

The journey begins with an insightful examination of the fundamental concepts in Chapter 1, unraveling the complex landscape of cardiac remodeling and its profound implications for cardiac health and disease. The narrative navigates through the physiological aspects of cardiac modeling in Chapter 2, shedding light on the effects of exercise and other influential factors.

Chapters 3 through 23 provide a nuanced understanding of specific elements shaping cardiac remodeling. From the prognostic indicators of unfavorable remodeling to the intricate roles of neurohormones, cardiokines, and the comparative effects of fatty acids and glucose, each chapter contributes a unique perspective to our comprehension of cardiac dynamics.

This book explores the roles of vitamins, minerals, and nutraceuticals in Chapter 7, highlighting their cardioprotective functions. In Chapters 8 and 9, the focus shifts to the molecular level, uncovering the roles of junctional adhesion molecules and ion channels in maintaining the integrity and functionality of the heart.

As we delve deeper into cellular components, Chapters 10 through 13 elucidate the significance of NOTCH signaling molecules, neuregulin-1, endoplasmic reticulum stress, and pattern recognition receptors in driving cardiac function and dysfunction. The involvement of myocardial contractile proteins, the growth and proliferation of cardiomyocytes, and the intricate network of cardiac endothelial cells are unraveled in subsequent chapters.

Furthermore, this book explores the roles of cardiac stem cells, pericytes, macrophages, and neutrophils in remodeling a diseased heart. Extracellular vesicles take center stage in Chapter 22, providing insights into their influence on cardiac dynamics.

The final chapter, Chapter 23, delves into the emerging research frontier—the regulatory roles of long noncoding RNAs and miRNAs in cardiac disease. This promising area can potentially reshape our understanding of cardiac remodeling at the molecular level.

Cellular, Molecular, and Environmental Contribution in Cardiac Remodeling is a comprehensive resource for researchers, healthcare professionals, and enthusiasts, providing a holistic view of the cellular and molecular intricacies governing cardiac remodeling. As we embark on this journey, we invite readers to explore the fascinating interplay between cellular elements, molecular signaling, and environmental factors in shaping the heart’s destiny.

We thank Elsevier for publishing this book and everyone involved in ensuring its outstanding quality, including Billie Jean Fernandez, Tracy Lange, and Kathy Padilla of Elsevier, for their unwavering support during manuscript preparation.

Dr. Rahul Mallick

A.I. Virtanen Institute for Molecular Sciences,

Faculty of Health Sciences,

University of Eastern Finland,

Finland

Professor Asim K. Duttaroy

Department of Nutrition,

Faculty of Medicine,

University of Oslo,

Norway

Chapter 1: Cardiac remodeling

Impacts on cardiac health and disease

Abstract

Cardiac remodeling is a response to cardiac demand or damage. Cardiac remodeling is associated with cardiac dysfunction and arrhythmia. The pathophysiology of different driving factors for cardiac remodeling and pharmacological strategies are discussed. Cardiac remodeling is also related to the development and progression of ventricular dysfunction, arrhythmias, and poor prognosis. The latest developments in cardiac remodeling and its impact on heart health and disease progression have been discussed in this chapter.

Keywords

Arrhythmia; Heart failure; Pathological cardiac remodeling

Abbreviations

ECG   Electrocardiogram

GFR   Glomerular filtration rate

TGF-β   Transforming growth factor-β

Keynotes

• There are two types of cardiac remodeling, physiological and pathological, which vary in their underlying molecular mechanisms, cardiac phenotype, and prognosis.

• Hemodynamic overload causes cardiac hypertrophy to maintain contractility and decrease wall stress into the ventricle. But prolonging this adaptive response may transit into heart failure via pathological remodeling.

• Volume overload results in eccentric hypertrophy, whereas concentric hypertrophy is due to pressure overload.

• The type of cardiac remodeling and the downstream signaling pathways determine the fate of cardiac hypertrophy, which could be either physiological or pathological.

• Structural or functional impairment of ventricular filling and/or blood ejection is considered heart failure. Coronary artery disease, hypertension, and diabetes mellitus are the three major causes of heart failure.

• Clinically, when the heart cannot pump sufficient blood to meet the metabolic requirements, it is defined as congestive heart failure.

• Congestive heart failure is characterized by diminished cardiac output, leading to venous congestion and poor systemic perfusion.

• Elevated BNP or NT-proBNP establishes the diagnosis of heart failure. Hyponatremia indicates a poor prognosis of heart failure.

• Simultaneously, using nondihydropyridine calcium channel blockers with beta-blockers can cause complete heart block.

• Treatment for heart failure often involves the use of various medications, such as beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor–neprilysin inhibitors, aldosterone antagonists, hydralazine combined with nitrate, and sodium-glucose cotransporter 2 inhibitors. These medications have been shown to improve the prognosis of heart failure. Diuretics and digoxin improve symptoms of heart failure and significantly reduce the number of hospitalizations.

• Regularly monitoring blood electrolyte levels (K+ and Na+) is mandatory if the patient takes diuretics.

• Therapeutic targeting of hypertrophy is crucial to enhance the fates of pathological cardiac remodeling and ultimate heart failure.

1. Introduction

The heart's primary function is to maintain blood perfusion to the peripheral organs to meet their needs under both normal and stressed conditions. The heart must remodel during unfavorable conditions to maintain the uninterrupted blood supply to the periphery. In 1982, Hockman and Buckey used the term remodeling for the first time to characterize the formed scar tissue following myocardial infarction.¹ In the following years, the term was used in various heart clinical conditions, which led to defining cardiac remodeling at an international consensus in 2000. Cardiac remodeling was described as a group of cellular, molecular, and interstitial changes that clinically manifest as changes in size, shape, and function of the heart resulting from cardiac injury.² Cardiac remodeling is also referred to as ventricular remodeling..³ Whereas cardiomyocytes are the fundamental cell population in the heart involved in the remodeling process, the role of fibroblasts, collagen (type I and III), interstitium, and coronary vessels is inevitable. The influence of hemodynamic load, neurohormonal activation, and other factors on cardiac remodeling require more investigation. The forum classified cardiac remodeling into physiological and pathological cardiac remodeling. Despite having different etiological pathways, both cardiac remodeling processes share several molecular, biochemical, and mechanical events.⁴ In this chapter, pathological cardiac remodeling has been focused.

2. Physiological cardiac remodeling

Physiological cardiac remodeling starts from the development of the heart in fetal life (strictly at which week of life), through infancy, and ends in the adult heart. The heart starts to maintain circulation in embryonic development. Metabolic pathways support tissue homeostasis and change in cellular phenotype.⁵ Physiological cardiac remodeling results in cell size growth, defined as cardiac hypertrophy.⁶ The heart enlarges in size in proportion to rising plasma volume and body weight during gestation with remarkable alteration in cardiac metabolism.⁷ Developing the heart highly depends on glucose metabolism due to low mitochondrial abundance, low-fat oxidation capacity of fetal cardiac mitochondria, and a low circulatory workload.⁸ The fetal heart relies on glucose (50%–70%) and lactate (around 30%) for energy metabolism.⁹–¹² Notably, lactate oxidation in the fetal heart is interrupted by the availability of fatty acids but not glucose.¹¹ The low blood glucose level in the fetus can cause disorganized developmental layers, aberrant looping, reduced myocardial thickness, vascularity, and heart rate, ultimately leading to cardiomegaly and heart failure in newborns.¹³,¹⁴ Fascinatingly, the high blood glucose level in the fetus with poor maternal glucose control may inhibit cardiac maturation by inducing excessive nucleotide biosynthesis through the pentose phosphate pathway.¹⁵ Therefore, the fetal heart stores glycogen in high concentration to fuel metabolism, produces nascent myocardial tissue, and maintains ATP synthesis. The glycolytic pathway of cardiac metabolism switches to the oxidative phosphorylation pathway with the transition to the neonatal period.¹⁶,¹⁷ Due to epigenetic reprogramming, in the adult heart, oxidative phosphorylation contributes to almost 95% of its ATP requirements to support its energetic needs.⁵

3. Exercise-induced cardiac remodeling

Exercise-induced cardiac hypertrophy was distinguished first in the late 19th century and described initially in the mid-20th century.⁵ Slightly increased or unchanged systolic and diastolic are accompanied by reversible cardiac remodeling.¹⁸,¹⁹ Improved cardiac output (the amount of blood volume ejected from the heart) during endurance running causes eccentric cardiac remodeling (Fig. 1.1), while upregulated systemic arterial pressures due to weightlifting induce the concentric formation of cardiac remodeling.²⁰,²¹ However, exercise-induced cardiac remodeling can protect the heart from ischemia–reperfusion injury. Still, this adaptation can increase stroke volume (the blood pumped by the left ventricle in a single heartbeat), which may cause fibrosis, harmful ventricular remodeling, and atrial or ventricular fibrillation.²²–²⁷ Notwithstanding, exercise can complement cardiac remodeling to improve health.

4. Pregnancy-induced cardiac remodeling

Similarly, pregnancy causes reversible cardiac remodeling by increasing stroke volume, heart rate, and cardiac output.²⁸–³⁰ This type of cardiac remodeling is eccentric, evident during the second and third trimesters of pregnancy.³¹ Surprisingly, despite being a reversible condition, longer QT interval in electrocardiogram (ECG), risk for arrhythmias, and mild systolic and diastolic dysfunction are frequently associated with pregnancy.⁵ Furthermore, pregnancy-induced cardiac remodeling is devoid of fibrosis and protected from stress.

5. Pathological cardiac remodeling

Pressure overload, volume overload, myocardial infarction, metabolic diseases, and aging can cause pathological remodeling.⁵ Fig. 1.2 illustrates the pathological cardiac remodeling. Fetal genes are activated in the heart, and substrate preferences are shifted from fatty acid to glucose during pathological cardiac remodeling.³²–³⁴ However, pathological remodeling of the diabetic heart is associated with left ventricular hypertrophy, diastolic dysfunction, increment of fatty acid and ketone oxidation, reduction of glucose oxidation, glycolysis, and lactate oxidation.³⁵–⁴⁰

6. Hypertensive left ventricular remodeling

A transition from adaptive to maladaptive changes during pathological cardiac remodeling may lead to ventricular dysfunction and heart failure.⁴¹ Around 75% of heart failure patients have precedent hypertension.⁴² The pressure overload from hypertension induces hypertrophy of terminally differentiated cardiomyocytes, leading to thickening and stiffening of the ventricular wall.⁴³ According to Laplace's law, ventricular wall stress is commensurable to ventricular pressure and cavity radius and inversely commensurable to wall thickness.⁴³ Increased wall thickness reduces wall stress and oxygen demand. If the pressure stress persists, the adaptive hypertrophic state of the myocardium decompensates to the state of clinical heart failure (Table 1.1). Short-term hypertrophic remodeling is adaptive to compensate for wall stress and oxygen demand. However, persistent, long-term stimuli are detrimental. The underlying mechanism of this transition remains unclear. Evidence suggests that the progression of heart failure might be blocked by suppressing pathological hypertrophic processes.⁴⁶–⁴⁸

Figure 1.1  Cardiac remodeling phenotypes. Depending on the stimuli, heart can remodel physiologically or pathologically. As the main cell type of heart, cardiomyocytes may induce either eccentric or concentric cardiac remodeling. Eccentric cardiac remodeling leads to lengthening of cardiomyocytes. Concentric cardiac remodeling is characterized by a reduction in left ventricular chamber dimension with cardiomyocyte hypertrophy.

7. Atrophic cardiac remodeling

In certain mechanical states (such as mechanical support with an LV assist device, prolonged bed rest, weightlessness during space travel) or under raised catabolic conditions, for example, in cancer, the heart can reduce left ventricular mass, manifesting not only hypertrophic but also atrophic changes.⁴⁹–⁵¹ Magnitude, duration, and inciting factors to cause atrophic remodeling.⁵² Short-term atrophic remodeling is mechanically beneficial to reverse hypertrophic state, but the prolonged state is associated with reduced cardiac performance and increased fibrosis.⁵³

8. Ventricular remodeling in myocardial infarction

Coronary heart disease is the leading cause of heart failure with reduced ejection fraction (the percentage of blood pumped by the left ventricle during each contraction).⁵⁴ The location and extent of myocardial tissue damage determine the magnitude of left ventricular remodeling.⁵⁵ With time, the infarct area expands, wherein unremitting mechanical forces stretch the abnormally stressed tissue, leading to an ineffective contractile performance with dilated left ventricle.⁴⁶

Figure 1.2  Mechanisms and therapeutic interventions of pathological cardiac remodeling. In response to pathophysiological stimuli, various cellular and molecular processes contribute to cardiac remodeling. Cardiomyocyte loss via cell death pathways such as necrosis, apoptosis, or possibly excessive autophagy; hypertrophic cardiomyocytes due to biomechanical and neurohumoral activation; fibrosis through accumulation of excessive extracellular matrix; insulin resistance; proarrhythmic phenotype due to alterations of ion channels. All these ultimately lead to heart failure. Even, haemodynamic unloading may cause cardiac atrophy by reducing myocardial mass, increasing protein degradation and fetal gene expression. Pharmacological agents e.g., angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and mineralocorticoid receptor antagonists may reduce cell death, hypertrophy, and fibrosis. Even glucagon-like peptide-1 may be beneficial for metabolic derangements. Cardiac resynchronization therapies and implantable cardioverter-defibrillators are helpful target for electrophysiological remodeling events. Finally, cell replacement therapy might replenish lost cardiomyocytes.

Table 1.1

There are three steps of left ventricular remodeling in myocardial infarction. Cell death (through necrosis, apoptosis, or possibly autophagy) due to interruption of coronary blood supply is the primary stage of myocardial infarction. The contribution of cardiomyocyte proliferation and cardiac resident stem cells are insignificant to response to infarct-related waves of cell death.⁵⁶–⁵⁸ In the second stage, the immune response is triggered by releasing various proteins from dying cardiomyocytes into circulation that remove dead cells and pave the way for healing. In the final stage, inflammation resolute, cardiac fibroblasts proliferate and secrete extracellular matrix proteins to form a fibrotic scar with a significant tensile strength that replaces dead cells. Increased wall stress provokes this remodeling process progressively, resulting in cardiac myocyte hypertrophy in the infarct border zone, wall thinning, and chamber dilation. The prolonged adverse remodeling process reduces left ventricular ejection fraction with increased end-diastolic and end-systolic volumes.⁵⁴

9. Metabolic remodeling of the heart

With the beginning of insulin resistance and obesity-induced type II diabetes mellitus, cardiac fatty acid utilization increases, contributing to cardiomyocyte hypertrophy and death, ventricular dilation, interstitial fibrosis, and interruption of diastolic relaxation.⁵⁹ This type of cardiomyopathy is associated with distorted forkhead transcription factors activation, mammalian target of rapamycin, microRNAs, mitochondrial dysfunction, the unfolded protein response, proteasome activation, and autophagy.⁶⁰,⁶¹

10. Diagnosis

Echocardiography, ventriculography, tomography, magnetic resonance imaging, and positron emission tomography cardiac scans are primarily used to detect cardiac remodeling.⁶²,⁶³

Several biomarkers for cardiac remodeling have been identified so far (Table 1.2). Substitution of fatty acid for glucose is another characteristic of cardiac remodeling.⁶⁴

Table 1.2

11. Consequences

Ventricular dysfunction is the prime effect of cardiac remodeling due to excessive stimulation of the sympathetic system and the renin–angiotensin–aldosterone system to induce protein synthesis in cardiomyocytes and fibroblasts to cause cellular hypertrophy and fibrosis, growth factors, and metalloproteinases activation, hemodynamic overload, oxidative stress, and cytotoxic effect, leading to cell death by necrosis or apoptosis.⁶⁴

Cardiac dysfunction due to reduced calcium supply during systole and increased calcium in diastole, the consequence of decreased L-channels and ryanodine receptors, as well as reduced activity of calsequestrin and calmodulin kinase, are features of cardiac remodeling.⁶⁵,⁶⁶

Myocardial stiffness, worsening in coronary flow, diastolic dysfunction, and malignant arrhythmias are related to an imbalance between the synthesis and degradation of collagen during cardiac remodeling.⁶⁷–⁷⁰

Energy deficit also plays a vital role in cardiac dysfunction due to diminished β-oxidation, aberrant triglyceride accumulation, and lipotoxicity.⁷¹–⁷³

Accumulation of aberrant proteins and ultimate proteotoxicity due to lysosomal degradation of unnecessary cytoplasmic components are common consequences of cardiac remodeling.⁶⁴,⁷⁴

DNA damage, protein oxidation, lipid peroxidation, changes in proteins responsible for calcium transit, activation of metalloproteinases, apoptotic and hypertrophic signaling pathways, cellular dysfunction, and the proliferation of fibroblasts are associated with oxidative stress during cardiac remodeling.⁷⁵

Clinically, the condition is known as heart failure (a complex of signs and symptoms due to structural or functional impairment of ventricular filling and/or ejection of blood).⁷⁶

12. Congestive heart failure

The clinical syndrome, when the heart cannot pump sufficient blood to meet the body's metabolic requirements, is called congestive heart failure. There are several clinical conditions and terms based on pathology. Congestive heart failure with reduced stroke volume and ejection fraction (≤35%–40%) is defined as heart failure with reduced ejection fraction or systolic heart failure. Congestive heart failure with reduced stroke volume but average/reduced ejection fraction (40%–50%) is defined as heart failure with preserved ejection fraction or diastolic heart failure. Congestive heart failure due to left ventricular dysfunction (resulting in tissue hypoperfusion and increased pulmonary capillary pressure), right ventricular dysfunction (resulting in congestion of blood in the vena cava and peripheral veins, which increases venous hydrostatic pressure and results in peripheral edema, raised jugular venous pressure, ascites, and hepatomegaly), or dysfunction of both ventricles are called left heart failure, right heart failure, or biventricular (global) heart failure, respectively. Chronic compensated congestive heart failure patients could be asymptomatic or symptomatic but stable.

In contrast, an acute decompensated congestive heart failure patient's condition deteriorates suddenly a critical cardiac condition (e.g., myocardial infarction). Patients typically have several risk factors (the variables or attributes that increase the probability of developing disease(s) or injury) that contribute to developing congestive heart failure. The leading causes of congestive heart failure are coronary artery disease, hypertension, and diabetes mellitus (Table 1.3). Fig. 1.3 and Table 1.4 demonstrate the pathophysiology of congestive heart failure.

Fatigue, nocturia, tachycardia, arrhythmias, S3/S4 gallop (an S3 gallop indicates rapid ventricular filling, while an S4 gallop indicates ventricular hypertrophy) on auscultation, pulsus alternans as well as cachexia are the common feathers of heart failure.⁷⁷,⁷⁸ Symptoms of pulmonary congestion are common in left-sided heart failure, while right-sided heart failure's clinical features are increased central venous pressure and fluid retention (Table 1.5). Routine laboratory studies (complete blood count, basic metabolic panel [creatinine, Na+, HbA1c/glucose], liver chemistries [alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, direct and indirect bilirubin, total protein, and albumin], inflammatory markers [C-reactive protein, erythrocyte sedimentation rate], fasting lipid studies, thyroid stimulating hormone), cardiac biomarkers (natriuretic peptides [BNP or NT-proBNP], cardiac troponin T or I), chest X-ray, ECG, and transthoracic echocardiogram are commonly used to diagnose the heart failure. Following confirmation of congestive heart failure, underlying causes (consider coronary angiogram, chest imaging, and advanced cardiac imaging) and modifiable risk factors (hypertension, coronary heart disease) are approached.⁷⁶,⁸¹–⁹⁰ Elevated natriuretic peptides establish the diagnosis of heart failure.⁸⁵–⁸⁷ Hyponatremia indicates a poor prognosis of heart failure, while elevated C-reactive protein indicates acute infection or inflammation.⁸¹,⁸⁷ A transthoracic echocardiogram is the best initial imaging test to assess cardiac structure and function in heart failure. At the same time, a chest X-ray defines acute, new-onset, or suspected heart failure.⁸⁷,⁹¹–⁹⁵ However, ECG abnormalities in congestive heart failure are common but primarily nonspecific. Advise regular exercise, and lifestyle modifications for cardiac rehabilitation, treatment based on heart failure staging, associated conditions, and frequent follow-up are the approaches to managing heart failure patients. Patients should be assessed for evidence of decompensation and treated if present. Options for patient's refractory to first-line medical therapy are second-line medical therapy, invasive device therapy, heart transplant, mechanical circulatory support, and palliative care.⁸⁷ In general life, style modification (weight loss, exercise, cessation of smoking, alcohol consumption, and recreational drug use, immunization [pneumococcal vaccine and seasonal influenza vaccine]), patient/family education (diet and fluid restriction, self-monitoring and symptom recognition, awareness of travel precautions), treatment of comorbid conditions (e.g., hypertension, dyslipidemia, diabetes, iron deficiency, obstructive sleep apnea, coronary artery disease), and avoidance of drugs that may worsen congestive heart failure (such as antiarrhythmogenic medicine, calcium channel blockers, nonsteroidal antiinflammatory agents, thiazolidinediones, inhalation anesthetics) are necessary to reduce general risk factors that are known to lead to the progression of congestive heart failure or other comorbidities (e.g., diabetes mellitus, hypertension).⁸⁷,⁹⁴,⁹⁶–¹⁰¹ Based on the stage, medical treatment of heart failure can be initiated (Table 1.6). Sometimes, diastolic heart failure is presented with other comorbid conditions, which also need to be considered while treating diastolic heart failure (Fig. 1.4).

Figure 1.3  Pathophysiology of congestive heart failure. Renin-angiotensin-aldosteron system and sympathetic nervous system activation, ADH and BNP production due to diminished cardiac output try to compensate to restore cardiac output. Increased afterload and cardiac remodeling negatively affect cardiac output, while increased preload and tachycardiac have a positive effect on cardiac output. The net effect of these compensatory mechanisms are sufficient to restore cardiac output. If not, the cycle repeats.

Table 1.3

Table 1.4

Table 1.5

13. Therapeutic targets

Various therapeutic approaches affect the cardiac remodeling process.⁴ The effects of therapeutic approaches have been mentioned in Table 1.7.

14. Fibrosis

Cardiac fibrosis is an independent and predictive risk factor for heart failure in ischemic and nonischemic cardiomyopathy.¹³⁰–¹³² No therapeutic strategy has been developed to target cardiac fibrosis¹³³ specifically. However, therapies concerning cardiac fibrosis may be beneficial to treat ventricular remodeling, e.g., antifibrotic actions of angiotensin receptor blockers, histone deacetylases inhibitors, and statins are inevitable.¹³⁴–¹³⁷

15. Cardiomyocyte hypertrophy

There are no specific therapeutic agents to target hypertrophic response. But some pharmacotherapeutics such as neurohormonal blockers (catecholamines, angiotensin II, aldosterone), Ca²+ channel blockers, or preload (the extent to which heart muscle fibers are stretched before the onset of systole) reducing agents (e.g., vasodilators or diuretics) modulate hypertrophic response variably. Serine/threonine phosphatases, nongated Ca²+ influx/Ca²+ signaling, downstream effectors of rapamycin or G protein–coupled receptors, protein kinases, oxidative stress, and chromatin remodeling agents (e.g., histone deacetylases) might be beneficial to target cardiomyocyte hypertrophy.¹³⁸

16. Cardiomyocyte death

Different types of cell death occur within the heart. But it is not certain whether the types of cell death are distinct and discrete outcomes or the continuum of overlapped biochemical and molecular processes. However, selective inhibitors targeting apoptosis (caspase inhibitors), necrosis (mitochondrial permeability transition pore opening inhibitors), and necroptosis (necrostatin 1) have been used in heart.¹³⁹ Of note, clinically used pharmacotherapies, e.g., angiotensin II and norepinephrine blockers, are known to suppress cardiomyocyte apoptosis to reduce adverse cardiac remodeling processes and subsequent progression to heart failure.¹⁴⁰–¹⁴³

17. Vascular remodeling

Many clinical trials of therapeutic neovascularization with either gene or protein therapies have failed. It seems that a single growth factor will not be sufficient to promote neovascularization and limit the adverse remodeling process. Therefore, a combination of multiple growth factors would be beneficial to develop efficient proangiogenic therapies to reverse adverse cardiac remodeling.⁴⁶

18. Metabolic remodeling

There is no specific treatment for obesity and diabetes mellitus–induced cardiomyopathy. However, lifestyle changes such as weight loss or bariatric surgery have been associated with a reduction in left ventricular wall thickness and mass, which may be beneficial.¹⁴⁴ Nevertheless, glycemic stabilizers, weight loss orlistat (a gastrointestinal lipase inhibitor), and sibutramine (a monoamine reuptake inhibitor) have shown no significant effects on the heart.¹⁴⁵

Figure 1.4  Therapeutic considerations of complicated diastolic heart failure. Diastolic heart patients complicated with hypertension, type 2 diabetes mellitus, ischemic heart disease, atrial fibrillation, obesity, chronic obstructive pulmonary disease, and iron deficiency should be treated with sodium-glucose transport protein two inhibitor with/without diuretics.

Table 1.6

Table 1.7

Recent animal study shows that antioxidative and antiinflammatory proteasome inhibitor MG-132 benefits diabetic cardiomyopathy.¹⁴⁶ Also, phosphodiesterase-5 inhibitor with tadalafil reduces body weight, inflammatory response, and infarction size in ischemia/reperfusion injury model in obese, diabetic mice.¹⁴⁷

19. Conclusion

The impact of cardiac remodeling on healthy and diseased hearts is ineffable. The incidence and prevalence of cardiac remodeling rates due to various cardiac conditions are increasing worldwide due to various structural, functional, electrophysiological, cellular, and molecular events. Genetic, neurohumoral, environmental, and age-related influences control pathological outcomes. Anyhow, the definite successes achieved already, and the growing opportunity of the problem will evolve progression in this fascinating field.

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