Inflammation in Heart Failure

Inflammation in Heart Failure, edited by W. Matthijs Blankesteijn and Raffaele Altara, is the first book in a decade to provide an in-depth assessment on the causes, symptoms, progression and treatments of cardiac inflammation and related conditions. This reference uses two decades of research to introduce new methods for identifying inflammatory benchmarks from early onset to chronic heart failure and specifically emphasizes the importance of classifying at-risk subgroups within large populations while determining the patterns of cytokines in such classifications. Further, the book details clinical applications of the pathophysiological mechanisms of heart failure, diagnosis and therapeutic strategies. Inflammation in Heart Failure’s breadth of subject matter, easy-to-follow structure, portability, and high-quality illustrations create an accessible benefit for researchers, clinicians and students.

• Presents updated information and research on the relevant inflammatory mediators of heart failure to aid in targeting future translational research as well as the improvement of early diagnosis and treatment
• Provides research into better understanding the different inflammatory mediators that signal the underlying diseases that potentially lead to heart failure
• Contains 20 years of research, offering a brief overview of the topic leading to current opinions on, and treatment of, heart failure
• Provides a structured, systematic and balanced overview of the role of inflammation in heart failure making it a useful resource for researchers and clinicians, as well as those studying cardiovascular diseases

• Language: English
• Publisher: Academic Press
• Release date: Dec 5, 2014
• ISBN: 9780128004852

Book preview

Inflammation in Heart Failure

First Edition

W. Matthijs Blankesteijn

Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands

Raffaele Altara

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands

Table of Contents

Cover image

Title page

Copyright

Contributors

Preface

1: PATHOPHYSIOLOGY OF THE INFLAMMATORY RESPONSE IN HEART FAILURE

Chapter 1: Inflammation in Heart Failure with Preserved Ejection Fraction

Abstract

1.1 Introduction

1.2 Consequences of Limited Understanding of Pathophysiology in HFpEF

1.3 Underlying Causes of HFpEF

1.4 Adaptive Mechanisms in HFpEF

1.5 Inflammation in HFpEF

1.6 Oxidative Stress, Endothelial Dysfunction and Microvascular Disease

1.7 Conclusions

Chapter 2: Role of the Innate Immune System in Ischemic Heart Failure

Abstract

2.1 Introduction

2.2 Initiation of the Immune Response

2.3 Effectors of Innate Immunity

2.4 Reverse Remodeling

2.5 Clinical Implications: Is There a Causal Link Between Dysequilibrated Inflammation and Remodeling?

Chapter 3: The Role of Inflammation in Myocardial Infarction

Abstract

3.1 Introduction

3.2 Role of the Inflammatory Response Before MI

3.3 The Role of the Inflammatory Response in MI

3.4 Inflammation as a Pharmacological and Biocellular Target

3.5 Conclusions

Chapter 4: Cross Talk Between Inflammation and Extracellular Matrix Following Myocardial Infarction

Abstract

Acknowledgments

4.1 Introduction

4.2 Roles of Inflammation in the MI Setting

4.3 Cytokine and Chemokine Roles in LV Remodeling

4.4 MMP Roles in the Infarcted Myocardium

4.5 ECM Roles in the MI Setting

4.6 Matricryptins: ECM Fragments with Biological Activity

4.7 Future Directions

4.8 Conclusions

Chapter 5: Cross Talk Between Brain and Inflammation

Abstract

5.1 Cardiovascular Disease and Brain Disorders

5.2 Cross Talk Between Brain and Cardiovascular System

5.3 Conclusions

Chapter 6: Translation of Animal Models into Clinical Practice: Application to Heart Failure

Abstract

6.1 Introduction

6.2 Animal Models of Acquired Cardiomyopathy

6.3 Animal Models of Genetic Cardiomyopathies

6.4 Improvements in Animal Models (Table 6.2)

2: INFLAMMATORY BIOMARKERS

Chapter 7: Inflammatory Biomarkers in Post-infarction Heart Failure and Cardiac Remodeling

Abstract

7.1 Introduction

7.2 The Role of the Inflammatory Response in Repair and Remodeling of the Infarcted Heart

7.3 Specific Inflammatory Biomarkers as Predictors of Post-infarction Remodeling

7.4 Implementation of Biomarker-Based Strategies in Patients with Myocardial Infarction

Chapter 8: Technological Aspects of Measuring Inflammatory Markers

Abstract

Acknowledgments

8.1 Immunoassays Development and New Directions

8.2 Methodology and Instrumentation

8.3 MIA Implementation

8.4 The Immunoassay Market: Opportunities and Issues

Chapter 9: Molecular Imaging to Identify the Vulnerable Plaque: From Basic Research to Clinical Practice

Abstract

9.1 Introduction

9.2 Molecular Imaging of Inflammation

9.3 Molecular Imaging of Cell Death

9.4 Molecular Imaging of Remodeling

9.5 Molecular Imaging of Thrombosis

9.6 Molecular Imaging of (Micro) Calcification

9.7 Socioeconomic Impact of Molecular Imaging

9.8 Conclusion and Future Perspectives

3: TARGETING OF THE INFLAMMATORY RESPONSE

Chapter 10: Mineralcorticoid Receptor Antagonists

Abstract

10.1 Introduction

10.2 Molecular Basis for the Clinical Use of MR Antagonist in HF

10.3 Pharmacology of Mineralcorticoid Receptor Antagonist

10.4 Clinical Evidences

10.5 Conclusion and Future Perspectives

Chapter 11: PPARs as Modulators of Cardiac Metabolism and Inflammation

Abstract

11.1 Introduction

11.2 Peroxisome Proliferator-Activated Receptors

11.3 PPARs and the Control of Cardiac Energy Metabolism

11.4 PPARs and Cardiac Inflammation

11.5 Cross Talk Between Cardiac Metabolism and Inflammation

11.6 PPAR Agonists and Heart Failure Treatment

11.7 Conclusions and Perspectives

Chapter 12: Inflammatory Modulation by Statins and Heart Failure: From Pharmacological Data to Clinical Evidence

Abstract

12.1 Inflammation and Immune Cells

12.2 Endothelial Cells

12.3 Cardiomyocytes

12.4 Fibroblasts

12.5 A Summary of the Clinical Evidence

Chapter 13: Small but Smart: microRNAs in the Center of Inflammatory Processes During Cardiovascular Diseases, the Metabolic Syndrome, and Aging

Abstract

Acknowledgments

13.1 Introduction

13.2 Role of Inflammation-Related microRNAs in HF

13.3 microRNAs as Regulators of the Inflammatory Response During Atherogenesis

13.4 microRNAs in the Metabolic Syndrome

13.5 Circulating microRNA Profiles of Cardiovascular Diseases

13.6 Aging, Inflammation, and HF: Are There Shared microRNAs?

13.7 Conclusions and Future Perspectives

Chapter 14: The Role of Cytokines in Clinical Heart Failure

Abstract

Acknowledgments

14.1 Role of Inflammation in the Pathogenesis of HF

14.2 Inflammation as a Therapeutic Target in HF

14.3 Summary and Future Directions

Index

Copyright

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Contributors

Raffaele Altara     Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands, and Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

Jonathan Beaudoin     Massachusetts General Hospital, Boston, Massachusetts, USA

W. Matthijs Blankesteijn     Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands

Hans-Peter Brunner-La Rocca     Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands

Emmanuel Buys     Massachusetts General Hospital, Boston, Massachusetts, USA

Federico Carbone

Division of Cardiology, Department of Medical Specialties, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland

Department of Internal Medicine, University of Genoa School of Medicine, and IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

Arrigo F.G. Cicero     Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy

Evangelos P. Daskalopoulos     Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands

Lisandra E. de Castro Brás     San Antonio Cardiovascular Proteomics Center, and Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

Kristine Y. Deleon-Pennell     San Antonio Cardiovascular Proteomics Center, and Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

Uli L.M. Eisel     Department of Molecular Neurobiology, University of Groningen, and Department of Psychiatry, University Medical Centre Groningen, Groningen, The Netherlands

Elda Favari     Pharmaceutical Sciences Department, University of Parma, Parma, Italy

Nikolaos G. Frangogiannis     Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, USA

Stefan Frantz     Department of Internal Medicine I, University Hospital Würzburg, Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany

Olga Frunza     Department of Medicine (Cardiology), The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York, USA

Michael E. Hall     San Antonio Cardiovascular Proteomics Center; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, and Cardiology Division, University of Mississippi Medical Center, Jackson, MS, USA

Kevin C.M. Hermans     Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands

Stephane Heymans     Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

Rugmani Padmanabhan Iyer     San Antonio Cardiovascular Proteomics Center, and Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

Dennis H.M. Kusters     Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

Richard A. Lange     San Antonio Cardiovascular Proteomics Center, Jackson, MS, and Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA

Merry L. Lindsey     San Antonio Cardiovascular Proteomics Center; Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, and Research Services, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA

Yonggang Ma     San Antonio Cardiovascular Proteomics Center, and Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

Douglas L. Mann     Cardiovascular Division, Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO, USA

Fabrizio Montecucco

Department of Internal Medicine, University of Genoa School of Medicine

IRCCS Azienda Ospedaliera Universitaria San Martino–IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, and Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland

Anna Planavila     Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Barcelona, Spain

Chris P.M. Reutelingsperger     Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

Nicoletta Ronda     Pharmaceutical Sciences Department, University of Parma, Parma, Italy

Marielle Scherrer-Crosbie     Massachusetts General Hospital, Boston, Massachusetts, USA

Regien G. Schoemaker     Department of Cardiology, University Medical Centre Groningen, and Department of Molecular Neurobiology, University of Groningen, Groningen, The Netherlands

Blanche Schroen     Center for Heart Failure Research, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

Leon J. Schurgers     Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands

Jan Tegtmeier     Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

Robrecht Thoonen     Massachusetts General Hospital, Boston, Massachusetts, USA

Hiroe Toba

San Antonio Cardiovascular Proteomics Center, Jackson

Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA, and Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan

Marc van Bilsen     Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

Lieke van Delft     Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

Vanessa van Empel     Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands

Sara Vandenwijngaert     Massachusetts General Hospital, Boston, Massachusetts, USA

Johannes Weirather     Department of Internal Medicine I, University Hospital Würzburg, Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany

Andriy Yabluchanskiy     San Antonio Cardiovascular Proteomics Center, Jackson, and Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA

Francesca Zimetti     Pharmaceutical Sciences Department, University of Parma, Parma, Italy

Preface

W. Matthijs Blankesteijn; Raffaele Altara

Heart failure is a progressive condition that affects an increasing number of patient worldwide and severely impairs their physical capabilities and quality of life. Despite large scientific efforts, the molecular mechanisms that lead to heart failure are still far from elucidated. Therefore, diagnosis of this condition is difficult unless the patient has reached a progressed state, accompanied with clinical symptoms. A better understanding of the molecular mechanisms contributing to the earlier phases of heart failure development would therefore help to improve the diagnosis and therapy. The drugs that are currently used can slow down heart failure progression but cannot cure the patient; moreover, the effectiveness of these interventions may very much depend on the subtype of heart failure, as many patients suffering from heart failure with preserved ejection fraction show little benefit from therapies with proven efficacy in heart failure with reduced ejection fraction.

An example of a molecular mechanism that is involved in the development and progression of heart failure is inflammation. It was originally observed in the wound-healing response that takes place in the area of injury after myocardial infarction. There, the inflammatory response is crucial for the removal of the necrotic debris from the area of injury and helps to attract the cells involved in the formation of a scar. In the meantime, inflammation has been described in cardiac remodeling due to other causes, for example, hypertension, and is already activated early on in its development. This highlights the importance of inflammation as a common molecular pathway of heart failure, providing potentially interesting options for diagnosis and therapy. However, the clinical results of interventions in inflammatory pathways have been disappointing so far, underscoring the complexity of the inflammatory response and the need for a better understanding of its molecular mechanisms. Therapeutic targeting of inflammation will therefore likely require careful patient selection and precise timing of the intervention to become successful.

The purpose of this book is to provide the latest information on the role of inflammation in heart failure to researchers and advanced students in the cardiovascular diseases. To this end, we have invited experts in the field to provide a comprehensive and timely overview of their research areas. The book is structured into three sections, providing the reader with easy access to the information. In Section 1, which focuses on the pathophysiology of the inflammatory response in heart failure, an overview is provided of the extensive literature on the role of inflammation in heart failure, with a distinction between ischemia-induced heart failure and heart failure due to other causes. Specific emphasis is put on the role of the innate immune system and the interaction between the extracellular matrix and the inflammatory mediators. The cross talk between the inflammatory response in the heart and the brain is highlighted and the section is finalized with an overview of different animal models of heart failure and their advantages and restrictions for the study of this condition.

In Section 2, the focus is on inflammatory biomarkers. The section starts with an overview of multiple inflammatory mediators as biomarkers for adverse remodeling and heart failure. Next, the pros and cons of different analytical techniques for measuring panels of inflammatory biomarkers in a single sample are discussed. In the last chapter of this section, an overview of imaging modalities to visualize the inflammatory response is provided.

Targeting of the inflammatory response is the subject of the third section of this book. Here, we focus on the experimental and clinical evidence for the beneficial effects of interventions on mineralocorticoid receptor and peroxisome proliferator-activated receptors. The modulating effects of statins and the involvement of miRNAs in the control of the inflammatory response and their therapeutic potential are discussed. Finally, the results of clinical trials with anti-inflammatory agents are presented and interpreted in light of our current understanding of the inflammatory response in heart failure.

1

PATHOPHYSIOLOGY OF THE INFLAMMATORY RESPONSE IN HEART FAILURE

Chapter 1

Inflammation in Heart Failure with Preserved Ejection Fraction

Vanessa van Empel; Hans-Peter Brunner-La Rocca    Department of Cardiology, Maastricht University Medical Centre, Maastricht, The Netherlands

Abstract

Currently, heart failure (HF) is evenly split between HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Patients with HFrEF are treated with medications that target the neurohumoral and sympathetic nervous system (β-blockers, ACE-inhibitors, and mineralocorticoid antagonists). However, these therapies do not improve functional class or survival in HFpEF patients. The question, therefore, that arises is which underlying pathophysiological pathways are most important in HFpEF. Recently, it was suggested that inflammation plays the crucial role in HFpEF. This chapter discusses whether increased inflammation is independent of the etiology of heart failure, if there are disease-specific mechanisms, and in what way inflammation is of particular importance in HFpEF.

Keywords

Heart failure

Heart failure with preserved ejection fraction

Inflammation

Oxidative stress

Endothelial dysfunction

1.1 Introduction

Until recently, heart failure was considered as one syndrome with different underlying causes. Treatment, apart from underlying cause, was uniform, despite acknowledging that no treatment trials had been done in patients with heart failure with preserved left-ventricular ejection fraction LVEF (HFpEF) [1]. Heart failure was basically considered as a final common pathway with uniform pathophysiology, irrespective of underlying disease. However, all the studies supporting this concept have been performed in patients with heart failure and reduced LVEF (HFrEF), because it was thought to be the more advanced stage of heart failure in general. Apart from diseases such as hypertrophic or restrictive cardiomyopathies, HFpEF was considered as a less advanced stage of heart failure and to be a relatively rare disease. This, however, was to a large extent related to the lack of knowledge and relatively rare use of echocardiography to measure LVEF in elderly patients who comprise the majority of HFpEF patients. Over the years, it became more and more evident that nearly half of the patients with the clinical syndrome of heart failure have normal or preserved LVEF, thus HFpEF [2]. Still, it took years before it became evident that HFpEF and HFrEF may have quite distinct underlying pathophysiology. For more details on the pathophysiology of HFrEF, see Chapters 2 and 3 of this book.

1.2 Consequences of Limited Understanding of Pathophysiology in HFpEF

Treatment that was shown to be highly efficacious in HFrEF patients [3] failed to show beneficial effects in HFpEF patients [4,5]. Even more so, intensifying similar therapy in HFrEF and HFpEF led to completely different results. Thus, whereas intensifying heart failure medication based on NT-proBNP guidance resulted in significant reduction of heart failure hospitalization-free survival, the opposite was the case in patients with HFpEF [6]. The question, therefore, that arises is which underlying pathophysiolocial pathways are most important in HFpEF that obviously are less or not important in HFrEF; information in this regard is, however, limited.

The limited understanding in the pathophysiology of HFpEF not only makes treatment difficult, but also makes diagnosis difficult (Figure 1.1). The current diagnostic algorithm of HFpEF focuses on symptoms and signs of HF in addition to evidence of diastolic dysfunction on imaging, usually echocardiography [3]. Yet, symptoms in HFpEF are nonspecific and echocardiographic measures correlate poorly with actual LV (left ventricle) filling pressure and lack accuracy [7,8]. Moreover, an important assumption was the fact that the important pathophysiological pathways are equal in all HFpEF patients as it is the case in HFrEF—at least to a large extent. So far, this has not yet been proven in basic research or in clinical studies. Better characterization may be helpful in this regard, which may include determination of underlying cause and investigation of myocardial and systemic consequences of these causes. Biomarkers may be helpful in this regard. Levels of brain natriuretic peptide (BNP) or its N-terminal propeptide (NT-proBNP) were suggested as additional diagnostic aids in the HFpEF workup [3]. Their value is proven for diagnosis in acute decompensated heart failure [9,10] as well as risk stratification [11] and guiding therapy [12,13] in chronic HFrEF, but the use of BNP and NT-proBNP is less well established in HFpEF [14]. Several other biomarkers may be helpful in this regard and may provide information on the pathogenesis of HFpEF as compared to HFrEF and may, therefore, help in a better understanding as well as in improving diagnosis of HFpEF and risk stratification.

Figure 1.1 Pathophysiology of HFpEF. Blue background indicates involvement of inflammation. HFpEF, heart failure with preserved ejection fraction; LV, left ventricular.

1.3 Underlying Causes of HFpEF

Different etiologies lead to heart failure and may differ between HFpEF and HFrEF. Patient characteristics and risk factors of HFpEF differ significantly from those of HFrEF (Figure 1.2). HFpEF patients are likely to be older and more often are female compared to HFrEF patients [15]. Furthermore, cardiovascular and noncardiovascular comorbidities are highly present in HFpEF patients and may significantly contribute to the patients’ limitations [16]. In a population study in Olmsted County, hypertension was prevalent in 63% of HFpEF compared to 48% in HFrEF patients and atrial fibrillation in 41% of HFpEF compared to 28% in HFrEF [2]. Interestingly, the presence of atrial fibrillation may identify a HFpEF cohort with more advanced disease and a significantly reduced exercise capacity compared to HFpEF patients without atrial fibrillation [17]. The prevalence of cardiovascular comorbidities varied in the different studies, depending on the type of study and the different criteria used to diagnose HFpEF. Overall, data from population-based studies, registries, and randomized control trials reported in HFpEF a prevalence of coronary artery disease of 20-76%, diabetes mellitus of 13-70%, atrial fibrillation of 15-41%, and hypertension of 25-88% [18]. However, studies comparing HFpEF with HFrEF all reported an increased prevalence of hypertension and atrial fibrillation in HFpEF and a decreased prevalence of coronary artery disease compared with HFrEF.

Figure 1.2 Comorbidities involved in HFpEF. Blue background indicates involvement of inflammation. Although one can discuss whether inflammation is involved in aging since aging is associated with increased comorbidities itself. HFpEF, heart failure with preserved ejection fraction.

There are additional cardiac and cardiovascular mechanisms that could contribute to the clinical picture of HFpEF. Thus, not only tachyarrhythmias (i.e., usually atrial fibrillation), but also bradyarrhythmia may cause symptoms of heart failure, such as exercise intolerance and dyspnoea [19]. In severe bradycardia, this is obvious clinically, although little prospective studies are done in this regard. However, chronotropic incompetence—lack of increase in heart rate during exercise—may play an often unrecognized role [20,21]. Moreover, pulmonary hypertension (PH) may also play a role in such patients. It is known that pulmonary artery pressure is often slightly elevated in patients with HFpEF [22]. As most data come from echocardiographic studies, it is difficult to distinguish if this increase is purely passive, that is, caused by increased pressure in the left atrium with consecutive increase in pulmonary venous pressure, or (additionally) caused by an increase in pulmonary vascular resistance. Invasive measurement in small trials suggested that increase in left-ventricular filling pressure, particularly during exercise, causes symptoms, although pulmonary vascular resistance was also slightly above the normal range [23]. However, invasive measurements at rest in a relatively large cohort of HFpEF patients revealed a substantial number of these patients having both increased pressure in the left atrium and significantly elevated pulmonary vascular resistance [24]. Finally, coronary artery disease is the more common cause of HFrEF, but myocardial ischemia also causes diastolic dysfunction. Thus, coronary artery disease can be a reason for HFpEF.

Although also common in patients with HFrEF, noncardiovascular comorbidities are more often associated with HFpEF, such as renal impairment, liver disease, peptic ulcer disease, and hypothyroidism [25]. Additionally, HFpEF patients typically have a higher body mass index (BMI) and are more likely to be obese [2]. Obesity is paradoxically associated with higher survival rates in heart failure. When comparing HFrEF with HFpEF, the obesity paradox was present in both with the highest survival rates in patients with BMI between 30.0 and 34.9 kg m− 2 [26]. Because HFpEF is highly associated with comorbidities, many of which significantly contribute to symptoms, this triggered a discussion whether HFpEF was merely a combination of comorbidities or a distinct disease. When comparing a community-based cohort of HFpEF patients and control patients without HF, fundamental cardiovascular structural and functional abnormalities were seen, however, even after accounting for body size and comorbidities, demonstrating that HFpEF is more than just a compilation of comorbidities [27].

The increased prevalence of comorbidities in HFpEF was also demonstrated when calculating the Charlson Comorbidity Index, a method of predicting mortality by classifying or weighting comorbid conditions [28]. Thus, the Charlson index was 3 or more in 70% of HFpEF patients [18]. Ather et al. studied the impact of noncardiac comorbidities on prognosis and mortality [29]. Although they studied a cohort of veterans, which was predominantly males, the HFpEF population was older, and had a high prevalence of diabetes, hypertension, obesity, and chronic obstructive lung disease. The overall hospitalization rates were similar for those with HFpEF compared with HFrEF, however there was a higher noncardiac hospitalization rate in HFpEF compared with HFrEF [29]. In general, HFpEF patients have a higher noncardiovascular cause of death, and HFrEF patients more often die of cardiovascular cause [30,31]. Although a majority of studies report a similar mortality rate in HFpEF and HFrEF, a meta-analysis by Somaratne and associates, including 7.688 HFpEF patients and 16.831 HFrEF patients from 17 studies, reported a 50% lower hazard mortality in HFpEF compared to HFrEF [32]. However, it is worth noting that concerning HFpEF, community-based studies reported a higher noncardiovascular death and, in contrast, clinical trials reported a higher percentage of cardiovascular deaths. This could be due to the inclusion criteria of controlled clinical trials, where relative healthier patients are included compared to the total population. Moreover, diagnosis may be less accurate and more difficult in HFpEF as discussed above, which may be particularly true in community-based studies. Table 1.1 summarizes important underlying diseases in HFpEF as compared to HFrEF.

Table 1.1

Selection of Pathways Involved in the Pathophysiology of Heart Failure, Comparing HFpEF and HFrEF

SCD, sudden cardiac death.

Therefore, the important key question is whether HFpEF really is a uniform disease. Until recently, this has rarely been questioned even if HFpEF is increasingly recognized as significantly different from HFrEF. Recently, a paradigm shift was suggested, but this was again an attempt to explain HFpEF with one central underlying pathophysiological mechanism (see below), where inflammation plays the crucial role [33]. Therefore, the questions that arise are whether increased inflammation is independent of the etiology of heart failure, whether there are disease-specific mechanisms, and in what way is inflammation of particular importance in HFpEF.

1.4 Adaptive Mechanisms in HFpEF

Recently, there is emerging evidence that the adaptive mechanisms may differ between patients with HFpEF as compared to patients with HFrEF. Table 1.1 summarizes various pathways that have been found to be of importance in patients with heart failure, irrespective of reduced or preserved LVEF. Although not all these pathways are explored in detail in both HFpEF and HFrEF, and particularly comparing the two, it is obvious that many pathophysiological pathways are not equally affected in HFpEF as compared to HFrEF. Thus, response to therapy suggests that activation of the renin-angiotensin-aldosterone system as well as the sympathetic nervous system is much more important in HFrEF than in HFpEF. On the other hand, there is increasing evidence that inflammation as well as pathways closely related to inflammation such as oxidative stress, endothelial dysfunction, and microvascular dysfunction may play a different role in HFpEF as compared to HFrEF.

Still, it is important to keep in mind that clinically it seems likely that the different causes of HFpEF not only trigger common pathways in all patients with HFpEF, but they also significantly influence the disease process as a whole. Moreover, results in HFpEF are quite diverse for many pathways, which seem less to be the case in HFrEF (Table 1.1). Here, we focus on inflammation and pathways related to inflammation and discuss the potential relevance of them in HFpEF and some differences with HFrEF.

1.5 Inflammation in HFpEF

For many years, HFpEF was considered mainly to be a consequence of chronically increased afterload. The fact that left-ventricular hypertrophy (LVH) is significantly related to HFpEF, and reduction in LVH and clinical events act in parallel, to a large extent and independently of the type of antihypertensive drug used—with some exceptions—was support for a very prominent role of afterload increase in the development of HFpEF. Still, questions remained why not all patients with hypertension develop LVH and poor outcome, irrespective of the treatment of hypertension. This concept also includes the development of myocardial fibrosis and increased myocardial stiffness, resulting in treatment suggestions that are not different from those in HFrEF. However, large trials addressing this failed to show positive results [4,5,61]. Very recently, even spironolactone, which is thought to more specifically reduce myocardial fibrosis than blockade of the renin-angiotensin system, failed to show convincing benefit in HFpEF although some methodological problems may have negatively influenced the results [42]. Other factors have been proposed as outlined above, but none were sufficiently convincing to explain HFpEF.

More recently, a new concept has been proposed that poses inflammation as a result of multiple comorbidities central in the pathophysiology of HFpEF [33]. Indeed, the concept is attractive because it provides an explanation for the fact that comorbidities are not only very common in patients with HFpEF, but also seem to significantly influence the presence of HFpEF and outcome [62]. In fact, as discussed above, comorbidities are very common in patients with HFpEF because the average HFpEF population is elderly. Moreover, it has been shown that patients with significant obesity and diabetes mellitus, even at younger age, have a significantly increased risk to develop HFpEF, also in the absence of macrovascular disease. There is increasing evidence that this form of diabetic cardiomyopathy is related to microvascular disease, which is known to be a significant problem in diabetes mellitus in other organs and systems. Microvascular disease in turn may be triggered by inflammation. Inflammation takes place in basically all chronic diseases.

The basis for the new concept comes both from human and from animal studies. Moreover, independently of this new concept, inflammation has been considered for quite sometime as an important factor in the pathophysiology of HFpEF.

1.5.1 Inflammation in HFpEF Animal Studies

In the 1990s, inflammation was found to be increased in animal models of LVH in hypertensive models. Obviously, this was not yet named HFpEF. Still, in these animal studies, a cause-effect relationship between inflammation and fibrosis in LVH was suggested [63]. In models of spontaneous (SHR) and renovascular hypertension rats, inflammation (macrophages) and fibrosis was found co-localized in the perivascular region in these animals with pressure overload [63,64]. Alteration of adhesion molecules were suggested to play an important role in this. Thus, altered expression of Intercellular Adhesion Molecule 1 (ICAM-1) were found in chronic SHR, which was related to pressure overload [65]. In the renovascular hypertension model, the potential positive effect of angiotensin-blockade and mineralocorticoid receptor antagonism has also been suggested [66]. This seems important because blockade of the renin-angiotensin system as well as mineralocorticoid receptor antagonism have been found to be of limited value in HFpEF patients, at least if these drugs are used in an unselected cohort of HFpEF patients [4,5,42,61], as discussed elsewhere in this chapter. Later, changes in different inflammatory and fibrotic markers were found in a model of rapid increase of arterial blood pressure by suprarenal aortic banding. Interestingly, expression of mediators of macrophages and fibrosis varied significantly over time. Thus, whereas activation was seen early, suppression was present later (i.e., 28 days after banding) [67]. This was also related to diastolic dysfunction. Myocyte chemoattractant protein-1 (MCP-1) was activated early (peak day 3), whereas transforming growth factor (TGF-)β remained elevated also late (28 days). Whereas LVH was seen already after day 7 with increased fibrosis and myocyte hypertrophy, diastolic dysfunction with normal LVEF was present on day 28. All of these effects could be prevented by inhibition of MCP-1, suggesting that inflammation may play an important role in the early (pre-clinical) stage of LVH with diastolic dysfunction [67]. This is in line with a more recent study that investigated the early cellular mechanisms linking interstitial fibrosis with the onset of the tissue inflammatory response in a cardiac hypertrophy and failure model of angiotensin-II infusion with nonadaptive fibrosis [68]. This nonadaptive fibrosis seen in hypertrophy could be prevented by genetic depletion of MCP-1, whereas the development of hypertension, cardiac hypertrophy, and increased systolic function was seen in both wild-type and MCP-1 KO hearts, suggesting a specific role of the inflammatory response on the fibrotic response considered to be a central underlying mechanism of diastolic dysfunction in LVH. Chemokine receptor CCR2 seems to play an important role in the development of cardiac fibrosis in this model, resulting from accumulation of bone marrow-derived fibroblast precursors [69]. Moreover, overexpression of the murine renin transgene in a transgenic rat model, which depicts insulin resistance, results in salt-sensitive cardiac inflammation and oxidative stress, accompanied with myocardial fibrosis and diastolic dysfunction. This seems to play a particularly important role in female rats [70]. On the contrary, calorie restriction in DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross of Dahl salt-sensitive and Zucker rats, showed downregulation of ACE and angiotensin-II type 1 receptor as well as reduced inflammation. These obese rats have phenotype resembling HFpEF and calorie reduction attenuates obesity, hypertension, LVH, and diastolic dysfunction [71].

There is more evidence of the crucial role of inflammation in the development of HFpEF from different models. Thus, in DOCA-salt hypertensive rats, hypertension increased leukocyte extravasation into cardiac tissue, resulting in increased collagen deposition and ventricular stiffness [72]. In this, the anaphylatoxin C5a generated by activation of the innate immunity complement system, which is a potent inflammatory peptide mediator through the G-protein-coupled receptor C5aR (CD88) present in immune-inflammatory cells, including monocytes, macrophages, neutrophils, T cells, and mast cells, is critically involved. Thus, inhibition with the selective C5aR antagonist PMX53 attenuated inflammatory cell infiltration and reduced collagen deposition and ventricular stiffness [72]. Interestingly, new links between complement signaling and metabolism were found and demonstrated that aberrant immune responses may exacerbate obesity and metabolic dysfunction [73]. This is in line with the above-discussed link between obesity, inflammation, LVH and diastolic dysfunction in the DS/obese rate model [71], and Dahl-SS rat models of LVH with diastolic dysfunction that can be improved by calorie restriction [74]. On the contrary, exercise training, which is known to improve metabolic syndrome, has similar beneficial effects [75]. Altered metabolic homeostasis in adipose tissue promotes insulin resistance, type 2 diabetes, hypertension, and cardiovascular disease. Inflammatory and metabolic processes are mediated by certain proteolytic enzymes that share a common cellular target, protease-activated receptor 2 (PAR2), which was shown to be an important contributor to metabolic and inflammatory dysfunction and inhibition of it attenuated not only metabolic, but also cardiovascular dysfunction [76].

Interleukins (IL) were also found to be involved in the process of inflammation and diastolic dysfunction. Thus, IL-16 was found to be elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight, and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in this model. In transgenic mice, enhanced cardiac expression of IL-16 induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis [77]. Similarly, IL-18 overexpression in rats fed by fructose to induce metabolic syndrome using adenovirus encoding rat IL-18 had comparable effects [78]. A blockade inhibited the development of fibrosis and diastolic dysfunction in spontaneous hypertensive rats [79]. However, the simple assumption that inflammatory cytokines only mediate adverse effects in models of HFpEF has recently been challenged [80].

1.5.1.1 Interactions with Other Systems

There are significant interactions with other systems. On the one hand, various factors may stimulate or suppress inflammation. On the other hand, inflammation has effects on the heart by different pathways, of which fibrosis and changes in the extracellular matrix (ECM) are very prominent ones as described above. Another important result of inflammation is the inhibition of NO bioavailability, which may in turn decrease protein kinase G (PKG) activity, thereby inducing concentric remodeling of the left ventricle, as recently described in detail [33]. The mechanisms of peroxynitrite production, reduced NO availability, and lower soluble guanylate cyclase (sGC) activity are described below.

There is, however, evidence that reduced NO, cGMP, and sGC may not only be a consequence of inflammation and oxidative stress, respectively, but that they may also lack inhibition of inflammation. Thus, the natriuretic peptide receptor A (NPRA), which if stimulated increases cGMP, has an important role in the regulation of fibrotic and inflammatory pathways in LVH. NPRA deletion in KO mice causes salt-resistant hypertension, LVH, and fibrosis [81] and increased expression of fibrotic genes such as collagen, metalloproteinases, transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) [82]. Deletion of the BNP gene (Nppb −/−) may cause focal cardiac ventricular fibrotic lesions and increase ventricular expression of profibrotic genes, including ACE, TGF-β3, and pro-α1-collagen [83]. BNP can upregulate the production of pro- and anti-inflammatory molecules such as reactive oxygen and nitrogen species, leukotriene B4, and prostaglandin E2; increase IL10 levels; and affect cell motility of monocytic THP1 cells [84]. Moreover, co-culture of peripheral blood mononuclear cells (PBMC) from cardiac transplant recipients with BNP caused a reduction in pro-inflammatory cytokines (TNF-α, interleukin-6 (IL-6), IL-1a), while expression of anti-inflammatory and regulatory cytokines (IL-4, IL-5, IL-13) was preserved [85]. BNP was also able to directly oppose human monocyte migration to MCP1, but its ability to block MCP1-induced chemotaxis was attenuated in monocytes from HTN and HFPEF patients suggesting that this potentially beneficial anti-inflammatory function of BNP is likely compromised in chronic pressure overload and HFpEF [86]. Taken together, these studies suggest that natriuretic peptides and consequently sGC and cGMP play an important regulatory role in inflammation in HFpEF, which might also provide the opportunity for therapeutic intervention in HFpEF.

These studies from animal models fit very nicely in the above-mentioned new concept of inflammation-induced HFpEF [33]. However, the therapies tested so far in humans should have much more prominent, beneficial effects as there is a large amount of experimental evidence that inhibition of renin-angiotensin-aldosterone system has anti-inflammatory effects (e.g., Refs. [38,87,88]). Moreover, it is unclear which of all the pathways described is most important in mediating cardiac inflammation, fibrosis, and diastolic dysfunction as well as which interactions between all of these pathways, in relation to myocardial fibrosis and diastolic dysfunction, are pivotal. Many other pathways not (directly) related to inflammation have been described as playing an important role in the development of HFpEF. Finally, the impact of the chosen model is not clear, and it is also unclear which of these models are most relevant to the human situation. Obviously, this is particularly true for a controversial disease such as HFpEF.

1.5.2 Inflammation in HFpEF Human Studies

There are significant studies showing increased inflammation in patients with HFpEF. Obviously, most of these studies investigated systemic inflammation as measured by biomarkers of inflammation in peripheral blood [89] or inflammation in peripheral tissue, but not directly myocardial inflammation. There are, however, a few studies that also obtained human tissue from HFpEF patients [90]. These studies revealed structural and functional alterations in the myocardium that may be relevant to LVH, diastolic dysfunction, and HFpEF. Thus, systemic inflammation was suggested to gradually affect the cardiac vascular endothelium resulting in increased expression of endothelial adhesion molecules including VCAM1 in the heart [90]. VCAM and other endothelial adhesion molecules may lead to the activation and subendothelial migration of circulating leukocytes. HFpEF patients had high numbers of CD3, CD11, and CD45-positive leukocytes in the myocardium, increased inflammatory cell TGF-β expression, and increased levels of collagen I and III [90]. TGF-β is a very strong inducer of collagen production and stimulates the differentiation of fibroblasts into myofibroblasts. Moreover, activated myofibroblasts may themselves induce inflammation by producing cytokines and chemokines, which stimulate inflammatory cell recruitment and activation [91]. Therefore, it impacts the cardiac homeostasis of the ECM and intensifies fibrosis, predisposing to diastolic dysfunction and subsequent HFpEF, basically confirming findings from animal studies relevant to LVH and diastolic dysfunction.

There is a significant amount of data showing increased biomarkers of inflammation in patients with both HFrEF and HFpEF. Comparing biomarker levels in HFpEF versus HFrEF may help to uncover pathways that are of specific importance in HFpEF patients. There are, however, limited studies in this regard, particularly with respect to focus on inflammation. Whereas several studies have investigated biomarkers in HFrEF, the data in HFpEF is much more limited [92]. Additionally, most studies that have been performed in HFpEF are either cross-sectional or do not have a consecutive HF population with both preserved and reduced LVEF included. Furthermore, many studies only investigated a single biomarker or a group of markers with similar pathophysiological background. An important shortcoming of measuring biomarkers in the plasma, however, is the fact that it remains unclear, whether a given marker is causally involved in cardiac remodeling, whether it is