Fisiopatologia De La Falla Cardiaca.docx

Pathophysiology of Heart Failure Edit Tanai1,2and Stefan Frantz*2,3 ABSTRACT Heart failure is considered an epidemic disease in the modern world affecting approximately 1% to 2% of adult population. It presents a multifactorial, systemic disease, in which—after cardiac injury—structural, neurohumoral, cellular, and molecular mechanisms are activated and act as a network to maintain physiological functioning. These coordinated, complex processes lead to excessive volume overload, increased sympathetic activity, circulation redistribution, and result in different, parallel developing clinical signs and symptoms. These signs and symptoms sum up to an unspecific clinical picture; thus invasive and noninvasive diagnostic tools are used to get an accurate diagnosis and to specify the underlying cause. The most important, outcome determining factor in heart failure is its constant progression. Constant optimizing of pharmatherapeutical regimes, novel targets, and fine regulation of these processes try to keep these compensatory mechanisms in a physiological range. Beside pharmacological therapy, interventional and surgical therapy options give new chances in the management of heart failure. For the optimization and establishment of these and novel therapeutical approaches, complete and comprehensive understanding of the underlying mechanisms is essentially needed. Besides diagnosis and treatment, efforts should be made for better prevention in heart failure by treatment of risk factors, or identifying and following risk groups. This summary of the pathophysiology of heart failure tries to give a compact overview of basic mechanisms and of the novel unfolding, progressive theory of heart failure to contribute to a more comprehensive knowledge of the disease. © 2016 American Physiological Society. Compr Physiol 6:187-214, 2016.

Definition and Epidemiology Heart failure is defined as the inability of the heart to supply the peripheral tissues with the required amount of blood and oxygen to meet their metabolic demands. Pathophysiologically, the cardiac output (for a list of abbreviations see table 13) is in its absolute or relative amount low and/or has a pathological distribution. It leads to a clinical syndrome characterized by symptoms like dyspnea or fatigue, and signs such as elevated jugular venous pressure, tachycardia, or peripheral edema. Heart failure is mostly caused by an underlying myocardial disease; however valve diseases, endocardial, or pericardial abnormalities and disorders in the heart rate/rhythm may also result in cardiac malfunction. The clinical severity of heart failure is graded according to the New York Heart Association (NYHA) functional classification based on the clinical symptoms and physical activity of the patient (Table 1). The diagnosis of heart failure is generally made based on the Framingham criteria, which involve manifested symptoms and clinical signs of the patient (76) (Table 2). The diagnosis requires at least 2 major criteria, or 1 major criterion with at least two minor criteria. Two or more minor criteria are only accepted as diagnosis if they cannot be due to different organ failure like chronic lung disease [chronic obstructive pulmonary disease (COPD)], liver cirrhosis or nephrotic syndrome. Another classification of chronic heart failure was established by the American College of Cardiology (ACC) and

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the American Heart Association (AHA) to complement the NYHA functional classification. This classification is also based on the clinical signs and symptoms of the patient, thus comprises the concomitant diseases and risk factors as well, to estimate the progression stage and outcome of the disease (Table 3). Patients in stage A have no structural heart disease but an increased risk for developing heart failure over time. Risk factors include hypertension, diabetes mellitus, and/or a family history for cardiomyopathies. In this stage, risk factors should be identified and treated to prevent the development of heart failure. Stage B presents with a structural heart disease like myocardial infarction or valve disease in the patient’s history, although yet without clinical manifestations. In this stage, the therapeutic strategy involves specific therapy of the underlying cause and optimizing of risk factors. In stage C, clinically manifested heart failure occurs with the typical symptomatology of dyspnea, fatigue, and peripheral edema.

*Correspondence

to [email protected] Dept. of Internal Medicine I, University Hospital Wu¨rzburg, Germany 2 Comprehensive Heart Failure Center, University of Wu ¨rzburg, Germany 3 Universita ¨ tsklinik und Poliklinik fu¨r Innere Medizin III, Universita ¨ tsklinikum Halle (Saale), Halle (Saale), Germany Published online, January 2016 (comprehensivephysiology.com) DOI: 10.1002/cphy.c140055 Copyright © American Physiological Society. 1

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Table 1 New York Heart Association (NYHA) Functional Classification Class

Severity of symptoms and physical activity

I.

No limitation of physical activity. Ordinary physical activity does not cause undue breathlessness, fatigue, or palpitations.

II.

Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in undue breathlessness, fatigue, or palpitations.

III.

Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in undue breathlessness, fatigue, or palpitations.

IV.

Unable to carry on any physical activity without discomfort. Symptoms at rest can be present. If any physical activity is undertaken, discomfort is increased.

Table 2 Framingham Criteria for Congestive Cardiac Failure Major criteria

Minor criteria

Paroxysmal nocturnal dyspnea

Bilateral ankle edema

Basal crepitations

Dyspnea on ordinary exertion

(> 10 cm above the lung base) Third heart sound (S3 gallop)

Tachycardia (>120 bpm)

Cardiomegaly

Nocturnal cough

Increased central venous pressure

Hepato(Spleno)megaly

(>12 cmH2O in the right atrium) Jugular vein distension

Pleural effusion

Acute pulmonary edema

Decrease in vital capacity by one-third from max.

Hepatojugular reflux Weight loss >4.5 kg/5 days in response to treatment

Table 3 Classification of Chronic Heart Failure According to the American College of Cardiology Stage

Description

A: High risk for developing heart failure

Hypertension, diabetes mellitus, family history of cardiomyopathy

B: Asymptomatic heart failure

Previous myocardial infarction, left ventricle dysfunction, valvular heart disease

C: Symptomatic heart failure

Structural heart disease, dyspnoea and fatigue, impaired exercise tolerance

D: Refractory end-stage heart failure

Marked symptoms at rest despite maximal medical therapy

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In this stage, not only the primary disease should be properly treated, but a symptomatic therapy should be carried out to maintain the patient’s “physical capacity” and to reduce symptoms of cardiac congestion. Beside adequate medical treatment, a cardiac resynchronization therapy should also be discussed. Stage D means an end-stage heart failure, when the maximal supportive and causative therapy is unable to provide a stable state, and cardiac decompensation is not controllable, reducible, or reversible for a long time. Cardiac transplantation or mechanical circulatory support must be urgently considered and carried out. In conclusion, the definition of heart failure according to the European Society of Cardiology (ESC) Task force (2012) includes: (i) Symptoms of heart failure—at rest or during exercise and (2) objective evidence (preferably by echocardiography) of cardiac dysfunction (systolic and/or diastolic) at rest (both criteria 1 and 2 must be fulfilled), and (3) in case where the diagnosis is in doubt, response to treatment directed toward heart failure (82). Heart failure is a highly frequent, “epidemic” disease in the modern world putting constantly pressure on clinical and public health systems with its significant mortality, morbidity, and need for hospitalization. The lifetime risk of developing heart failure is approximately one in five for a 40-year-old in Europe and North-America (85). The main risk factors of heart failure include coronary artery disease (CAD), hypertension, diabetes mellitus (55), family history of cardiac diseases, obesity, chronic pulmonary diseases, or use of cardiotoxins. Among patients with diagnosed heart failure more than 50% present with low ejection fraction (EF) (i.e., HFREF=heart failure with reduced ejection fraction), and a little less than 50% have preserved systolic function, mostly by reduced diastolic performance (HF-PEF = heart failure with preserved ejection fraction). There are some remarkable epidemiological and etiological differences between HF-REF and HF-PEF, namely, patients with HF-PEF are mostly older, more often female or obese, and have hypertension or atrial fibrillation as an underlying cause of their cardiac dysfunction. It leads more often to cardiac decompensations and hospital admissions, therapy resistance and incompliance occur also more frequently (121). In contrast, the clinical population with HF-REF is mainly characterized by an exactly defined cardiac disease as a cause: CAD, uncontrolled hypertension, or heart valve failure. There are some differences in the incidence and prevalence of heart failure considering special populations of age, sex, and ethnicity. Studies on heart failure indicate that the prevalence and incidence of heart failure and its concomitant diseases are significantly higher in the older population (64). Traditionally, 65 years of age has been considered as cut-off age for the definition of elderly, here occurs in approximately 10% an impaired cardiac function. It is usually accompanied by severe complications, frequent hospitalizations, and different concomitant diseases. Heart failure has similar prevalence rate in both sexes, but there are some small differences in the development and specific features of the disease. Men

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have higher incidence and prevalence but also worse outcome. Women are significantly older (after menopause) at the time point of the diagnosis, but survive longer after all (2). They have higher prevalence and incidence of diastolic dysfunction, and/or hypertensive heart disease. Concerning the cause of heart failure, a specific geographical distribution can be drawn. In industrialized western countries, the most common cause of heart failure is an ischemic heart disease, mainly caused by a CAD. It is followed by arterial hypertension and valvular heart diseases. Rare diseases like Chagas’ disease or cardiomyopathies are more likely in developing countries. It should also be considered, that in developing countries the average patient age is significant lower and therapeutic efficiency and outcome of the disease are far poorer, compared to the western world. However, these clear differences seem to merge as a consequence of urbanization with its special features like the negative changes of the eating habits and a more sedentary lifestyle, which lead to a significant increase of diabetes, hypertension, or coronary heart disease (24). Heart failure is a progressive disease, associated with an annual mortality of approximately 10%. The main causes of death in patients with heart failure is sudden cardiac death (>50%) (63) or multiple organ failure due to the chronic systemic hypoperfusion. Despite rapidly developing therapy strategies, heart failure has still a poor outcome with nearly 25% to 50% mortality rate in 5 years after diagnosis. It is often caused by concomitant diseases especially by renal dysfunction, hypercholesterolemia, or anemia. Classic prognostic factors for poor outcome are valvular regurgitation, ventricular arrhythmias, higher NYHA functional classes, lower left ventricular EF, high level of N-terminal pro-B-type natriuretic peptide (NT-proBNP), or low serum sodium level; novel markers include autonomic dysfunction, oscillatory breathing pattern, and insulin resistance (100).

Pathophysiology of Heart Failure

Table 4 Etiology of Heart Failure Causes of systolic and diastolic heart diseases Causes of systolic heart diseases

Causes of diastolic diseases

Coronary artery disease

Coronary artery disease

Diabetes mellitus

Diabetes mellitus

Arterial hypertension

Arterial hypertension

Valvular heart disease

Valvular heart disease

Arrhythmia

Hypertrophic cardiomyopathy

Inflammatory diseases

Restrictive cardiomyopathy

Peripartum cardiomyopathy

Constrictive pericarditis

Congenital heart disease Medications, drugs (e.g., cocaine and doxorubicin) Idiopathic cardiomyopathy Causes of low-output and high-output heart failure Causes of low-output heart failure

Causes of high-output heart failure

Coronary artery disease

Hematological diseases: Anemia, Polycythemia vera, Beta-Thalassemia

Arterial hypertension

Hyperthyreosis, thyrotoxicosis

Cardiomyopathies

Beriberi (vitamin B1 depletion)

Valvular heart disease

Glomerulonephritis

Pericardial diseases

Skeletal diseases: Paget’s disease, McCune-Albright syndrome, Multiple myeloma Carcinoid syndrome Pregnancy (physiologic)

Etiology and Risk Factors The most common cause of heart failure is ischemic heart disease due to impaired myocardial perfusion, mostly caused by an acute or chronic myocardial ischemia. Other—still common—causes are cardiomyopathies (idiopathic or toxininduced, e.g., doxorubicin and alcohol), or valvular heart diseases. There is no accepted standard for the etiological classification of heart failure; it can be divided into many subcategories according to the affected functional phase, circulation system, volume status, etc. (Table 4). Risk factors include several medical states, which by themselfes are enough to cause cardiac dysfunction; mostly a combination of them occurs in patients with heart failure.

. High blood pressure

Extreme obesity Causes of left- and right-sided heart failure Causes of left-sided heart failure

Causes of right-sided heart failure

Coronary artery disease

Coronary artery disease (right ventricle MI)

Hypertension

COPD

Myocarditis

Pulmonary hypertension

Hypothyroidism

Pulmonary valve stenosis

Heart valve disease

Pulmonary embolism Neuromuscular disease

CAD, myocardial ischemia, and myocardial infarction

. Hyperglycemia, impaired glucose tolerance, and diabetes

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Hypercholesteremia

. Obstructive sleep apnea . Drug abuse and excessive alcohol consumption . Connective tissue disorders (systemic lupus erythematosus,

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EF is normal (called heart failure with preserved ejection fraction = HF-PEF), thus diagnosis and follow-up seem more difficult, than in systolic heart failure. It is usually related to chronic hypertension or ischemic heart disease but can be due to restrictive, infiltrative, or hypertrophic cardiomyopathies as well (19, 93).

sarcoidosis, and amyloidosis)

. Congenital heart defects . Family history . Smoking . Obesity . Viral infections . Arrhythmias

Classification Heart failure can be classified according to several pathophysiological or functional perspectives, such as the affected circulatory system (right-left), cardiac function (systolicdiastolic), or the underlying pathophysiological factor (pressure-induced/volume-induced).

Systolic versus diastolic heart failure For understanding the basic mechanisms and principles of the pathophysiology of heart failure, a clear definition and understanding of the primary mechanisms of systolic (HF-REF) and diastolic (HF-PEF) heart failure are essential. Systolic and diastolic heart failure are distinct syndromes with wellknown pathophysiology, symptomatology, and epidemiology. Not only differ development of impaired heart function, but also macro- and micromorphology of the heart, including the cardiomyocytes or the extracellular matrix structure. Systolic heart failure is characterized by an impaired left ventricular contractility, resulting in a reduced EF. Therefore, this syndrome is also called heart failure with reduced left ventricular ejection fraction (HF-REF). The most common underlying causes of systolic heart failure are ischemic heart disease, cardiomyopathies, and heart valve diseases. The main structural change is an eccentric remodeling that is followed by progressive chamber dilation, and therefore a volume-overload, leading predominantly to forward heart failure. In contrast to systolic, diastolic heart failure is accompanied by impaired ventricle relaxation and filling, increased ventricle stiffness, and therefore, an elevated filling pressure as a response of pressure overload. Diastolic heart failure is characterized by a concentric remodeling or ventricular hypertrophy resulting in pressure overload, and mainly backward heart failure. The

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Pressure-overload versus volume-overload heart failure Left ventricular dysfunction by pressure overload may develop due to adverse left ventricle chamber remodeling, decreased myocardial contractile function, or a combination of these. It mostly occurs in aortic valve stenosis and/or arterial hypertension. Volume overload refers to the state when the heart chambers are overfilled with blood, which they try to transmit into the systemic circulation. Various pathologies can lead to volume overload, such as arteriovenous malformations and fistula, congenital heart diseases (persistent ductus arteriosus and ventricular septal defect), or valvular heart diseases (e.g., aortic regurgitation and mitral regurgitation). The pulmonary circulation is also affected in valvular heart diseases (tricuspid regurgitation and pulmonary regurgitation) or in congenital atrial septal defect.

Low-output versus high-output heart failure Low-output means that the cardiac output (CO) fails to fulfill the blood and oxygen requirements of the peripheral tissues and cannot rise with exertion. The causes of low output heart failure can be divided into three groups: pump failure, excessive preload, or excessive afterload: 1. Pump failure (reduced inotropy) a. Systolic heart failure b. Relevant bradycardia c. Negative inotropic medications 2. Excessive preload (volume overload) a. Mitral regurgitation b. Aortic regurgitation 3. Excessive afterload (pressure overload) a. Aortic stenosis b. Hypertension High-output heart failure occurs when the CO is normal or elevated, to meet the increased requirements of the body, but still fails to meet demands (83). Volume overload results from chronic neurohumoral activation and progresses to ventricular dilation and structural remodeling over time. Clinically, high-output heart failure presents with tachycardia

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Pathophysiology of Heart Failure

Table 5 Compensatory Mechanisms and Their Exhaustion in Heart Failure Localization

Compensated

Decompensated

Cardiac

Frank-Starling mechanism

Reduced EF

Ventricular hypertrophy

Ventricular dilation

Tachycardia

Arrhythmias

Increased vascular tone

Vasoconstriction

Perfusion redistribution

Peripheral hypoperfusion

RAAS

Hypertension, vasoconstriction

Vasopressin (ADH)

Volume overload

Circulating catecholamines

Tachycardia

Natriuretic peptides

Hyponatremia

Increased sympathetic adrenergic activity

Tachycardia

Reduced vagal activity

Tachycardia

Vascular

Hormonal

Autonomic

jugular venous distension, and warm, sweaty skin. The clinical findings however depend strongly on the underlying disease. There are several physiological circumstances which may result in a hyperdynamic state, such as stress/anxiety, physical exercise, pregnancy, or fever (Table 5).

Unilateral heart failure: Right-sided versus left-sided heart failure Left- and right-sided heart failure are clinically separated syndromes; however, patients often present with a combination of left- and right-sided hear failure, what is called global congestive heart failure. This close relationship occurs due to the interdependence of the two connected circulatory systems of the heart: the systemic, “left” and the pulmonary, “right” circulatory system. In left-sided cardiac dysfunction the heart fails to maintain a continuous peripheral tissue perfusion with the required amount of blood. Not only the amount of blood volume is reduced, also the distribution changes. Thus compensatory mechanisms occur, for instance, the utilization of oxygen from the blood increases. The heart tries to compensate with an increased filling, thus systolic and diastolic pressure in the left atrium rises, causing an elevated pressure status in the pulmonary circulatory system. The pressureinduced fluid-leakage from the capillaries leads to chronic pulmonary congestion. The juxta-alveolar tension receptors become also activated and the elastic resistance increases, leading to the well-known symptoms and signs of left-sided heart failure. The reflex-tachycardia may, in contrast, lead to a vicious circle by additionally reducing the ability of the heart to contract effectively. Right-sided heart failure is characterized by a reduced blood supply mainly in the pulmonary

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circulation. In chronic cases, it shifts to the left atrium and reduces the systemic blood supply as well. To maintain a sufficient preload, the systolic and diastolic pressure rises in the right atrium, which leads to congestion in the gastrointestinal tract followed by anorexia, hepato-splenomegaly with/without ascites, and anasarca by increased hydrostatic pressure in the capillaries. Right ventricular heart failure often presents concomitant to a left ventricular dysfunction but can also exist as an isolated cardiac failure, as a result of a right ventricular myocardial infarction, chronic obstructive pulmonary disease, or pulmonary hypertension, or by rare diseases like severe tricuspidal regurge or arrhythmogenic right ventricle disease (128).

Signs, Symptoms, and Systemic Effects The wide spectrum of clinical manifestations in heart failure can be divided into two main groups, as right and left ventricle dysfunction, according to the affected circulatory system. Left ventricle dysfunction is primarily characterized by pressure overload in the pulmonary circulation resulting in pulmonary congestion with the subjective symptom of dyspnea and the clinical signs of pulmonary crepitations, compensatory tachycardia, and tachypnoe. The hypoperfusion in the systemic circulation occurs as a cardinal symptom in left ventricle dysfunction due to the impaired CO, and leads to renal dysfunction or malabsorption followed by cardiac cachexia. These clinical symptoms and signs are parts of a maladaptive reaction to the impaired heart function, occur often as a mixed clinical syndrome and result in frequent cardiac decompensations and/or multiple organ dysfunction. The cardinal symptoms of heart failure are unspecific, multifactorial, and occur often in patients with other underlying causes as well (e.g., pulmonary artery embolism). They can be observed during physical exertion in early stages, but later at rest as well. Not only heart failure incidence increases with age, but that of concomitant comorbidities, such as anemia, renal failure, or depression as well. These may be causally associated or independent from the heart failure itself, but have a great impact on the severity of the disease and on prognosis. The activated compensatory pathophysiological systems in heart failure affect mainly the myocardium, but lungs, kidneys, gastrointestinal tract, or peripheral vascular system as well. In general, heart failure is a systemic disease and affects all organ systems in the human body. Its signs and symptoms are often uniform, but the underlying pathophysiology can be quite diverse. Therefore, its treatment needs a holistic approach, taking into account different etiologies.

Pulmonary manifestations Pulmonary congestion Due to the increased alveolar capillary pressure, fluid transudation and accumulation develops in the pulmonary interstitium and perialveolar space, and pulmonary crackles

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or crepitations can be auscultated on the basis of the lungs. In mild heart failure, the induced lymphatic drainage transports the alveolar and interstitial fluid back to the venous side of the systemic circulation, but this compensatory mechanism exhausts over time. The congestion activates furthermore the juxtacapillary “J-receptors,” which induce rapid, shallow breathing with the subjective feeling of dyspnea. Milder form is a pleural effusion, when the elevated pleural capillary pressure results in fluid transudation into the pleural cavity, nevertheless if crepitations present extensively over both lung fields and are followed by expiratory wheezing, pulmonary edema occurs.

Dyspnea, orthopnea, bendopnea, and paroxysmal nocturnal dyspnea Besides pulmonary congestion, there are other factors, which may also induce and affect cardiac dyspnea, for instance anemia, increased pulmonary resistance, and diaphragm and/or respiratory muscle fatigue. If dyspnea occurs in a recumbent position, it is called orthopnea, and results from the redistribution of fluid from the lower extremities and splanchnic circulation into the cardiopulmonary circulation. Orthopnea may present more explicit by extreme obese patients or by patients with ascites or known pulmonary disease. It is usually relieved by sitting up or in a forward-leaning position. Novel form of dyspnea has been recently characterized: in bendopnea, shortness of breath occurs when bending forward, as a sign of excessive fluid retention. It is mediated via acutely elevated filling pressure in an already increased pressure state, especially if the cardiac index is reduced (119). Pulmonary nocturnal dyspnoea and nocturnal cough refer to the state when short periods of severe dyspnoea and coughing, wheezing attacks occur during the night. It may develop due to an increased pressure in the bronchial arteries that leads to compression in the airways, or because of increased pulmonary resistance by congestion. It is usually characterized by persistent wheezing; coughing without any relieving positions or maneuvers.

Cardiac asthma The most severe manifestation of acute congestive heart failure is cardiac asthma. It is characterized by severe wheezing, coughing, and dyspnea due to progressive bronchospasm. Bronchospasm is thought to occur as a combination of elevated bronchial and pulmonary vascular pressure, narrowed airways by reduced lung volume, and obstruction from intraluminal edema (68).

Cheyne-Stokes respiration The periodic Cheyne-Stokes respiration occurs typically in advanced heart failure, and is caused by the PCO2 insensitivity or depression of the respiratory center. The cycles of the respiration are made up of an apneic phase, in which—due to

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the central insensitivity—arterial PO2 falls and PCO2 rises in arterial blood gases. This constellation stimulates the central regulatory center and is followed by a compensatory phase of hyperventilation and a resulting hypocapnia. Hypocapnia induces an apneic phase again, triggering a new circle (66,89).

Cardiac symptoms Heart failure is often accompanied by cardiomegaly, the enlargement of the heart. It is best seen in chest X-ray, where the cardiothoracic index is significantly elevated (>50%). In cardiomegaly, the punctum maximum of the maximal impulse is usually displaced left-lateral, and may have a prominent palpable pulsation. The first heart sound is usually soft, especially if the patient is tachycardic. A third (94) or even fourth heart sound or protodiastolic gallop may also present in patients with heart failure. It is best audible at the apex and occurs mostly in volume overload. Moreover, murmurs of mitral or tricuspid regurgitation may be auscultated.

Vascular signs Vasculature The regulation of the vascular tone and thereby the adaptation to several mechanical changes and altered pathophysiological circumstances are regulated by the vascular endothelium. The elevated peripheral resistance or afterload in heart failure leads to activation of the neurohormonal system, such as to increased production of vasoactive molecules, in which the vascular endothelium plays an important role.

Jugular veins The filling of the jugular veins represents the right atrial pressure. It can be examined in a half-lying half-sitting position in 45 grades, with the head looking to the other side of the examined vein. It is expressed in centimeters of water, and normally takes around 8 to 10 cmH2O. Dilated jugular veins occur in advanced heart failure as a consequence of elevated abdominal pressure. It is often called positive abdominojugular or hepatojugular reflux sign and defined by a significantly increased jugular venous pressure (>12 cmH2O) for at least 15 s after abdominal (mainly in the liver region applied) pressure. Phlebectasia of the internal jugular vein can also occur in other conditions as well, for instance, in tricuspid stenosis, constrictive pericarditis, superior vena cava obstruction, or cardiac tamponade.

Anemia Heart failure increases both the incidence and prevalence of—usually moderate—anemia (8), in NYHA class II to III the prevalence of anemia makes up about 20%. Concomitant anemia is common especially in women, elderly patients, or patients with renal failure (117). The causes

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include decreased vitamin, iron, etc. absorption due to cardiac congestion, increased blood loss by an anticoagulative therapy, or chronic inflammation. Due to the existing anemia, oxygen transport, and/or oxygen utilization is depressed in tissues, which significantly reduces the physical capacity. According to the latest studies, iron supplementation appears to have a positive impact on anemia (FAIR-HF), in contrast, a pure anemia correction seems to be less promising; a final judgment however, will depend on the results of currently ongoing clinical trials (RED-HF, STAMINA-HeFT).

Extremities The cardinal manifestation of heart failure is peripheral edema. It occurs usually symmetric in the lower extremities (ankles and pretibial), or may present presacral or scrotal in bedridden patients. It is usually accompanied by skin pigmentation and induration over time, but disappears after diuretic therapy. Not only cardiac, but peripheral muscles react to heart failure. They respond with muscle mass reduction, reorganized muscle structure, and altered metabolic functions. Furthermore, the extremities are often cold and pale; the acres are cyanotic due to the vasoconstriction and centralization.

Gastrointestinal symptoms Patients with advanced heart failure may also suffer from gastrointestinal problems. Systemic congestion—including the bowels or the liver—is often accompanied by anorexia, nausea, or abdominal pain. In hepatomegaly, the congested liver is not only enlarged, but also often tender, even painful, and pulsating (12). As a result of the elevated hepatic vein pressure, ascites usually occurs. As a late sign, jaundice may develop, resulting from altered liver function, congestion, and from hypoxia due to impaired perfusion.

Cardiac cachexia Patients with advanced heart failure usually have peripheral muscle wasting, which is often restricted to the lower limbs (disuse atrophy) or affects the whole body and other tissues as well, called cardiac cachexia (10). The exact mechanism of cardiac cachexia, one of the severe manifestations of advanced heart failure, is not known, but there are some mechanisms which affect its development. Increased metabolic rate, nausea, vomiting, anorexia, malabsorption due to abdominal and liver congestion, and induced proinflammatory processes are certainly involved. Cardiac cachexia is associated with poor prognosis of the disease.

Renal failure Renal failure is an independent risk factor for heart failure, which strongly influences the clinical outcome of the disease. An increased salt and fluid retention by impaired renal function often leads to elevated filling pressure and systemic volume overload. Vice versa, low-output cardiac failure

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often causes decreased renal filtration rate by reduced blood flow, and through neurohumoral hyperactivity an impaired renal function. Therefore it is difficult to differentiate, what came first: heart failure (cardiorenal syndrome) or renal parenchymal disease causing cardiac dysfunction (renocardial syndrome) (107). It should be acknowledged that there is an overlap between these two syndromes. Cardiorenal syndrome occurs as a result of multiple mechanisms, some of them connected directly to heart failure (perfusion loss and impaired baroreceptor control) (4) and partially to risk factors (hypertension), or to pharmacotherapy (diuretics and ACE inhibitors) of heart failure. The mechanisms underlying the enhancement of cardiovascular mortality by primary kidney disease are not well defined. These include uncontrolled hypertension, inflammation, myocardial and vascular calcification, and oxidative stress. Renal function disorder is also thought to contribute and is connected to anemia in heart failure. Therefore, the validity of the—partially renal eliminated—heart failure marker BNP (B-type natriuretic peptide) and its precursor NT-proBNP for the severity of heart failure is reduced in renal failure (71, 129).

Cerebral symptoms Cerebral symptoms such as confusion, sleep disorders, dizziness, altered mood, or disorientation occur often in patients with heart failure, especially in elderly. The term “cardiogenic dementia” identifies the link between impaired cognitive function and cardiac dysfunction (28). This association with heart failure is a consequence of the shared risk factors, perfusion abnormalities, and rheological alterations. There are two main manifestations of impaired cerebral function (ICF): acute and fluctuating, known as delirium, which can be precipitated by an underlying medical illness; and chronic ICF mostly by stable heart failure. Some border zone manifestations are also known, such as the mild cognitive impairment (MCI) or cognitive impairment but no dementia (CIND). Compared with the general population, depression is up to five times more common in patients with diagnosed heart failure. Depression increases significantly morbidity and mortality and causes a major decrease in quality of life (43). The negative impact of depression on the course of the disease is multifactorial and cannot be attributed only to “impaired health behavior.” Indeed heart failure itself may influence other pathophysiological factors, like imbalance of the autonomic nervous system or inflammatory processes that secondary cause depression. In addition to psychotherapeutic treatments, antidepressants provide a therapeutic option, even though many agents are contraindicated due to their potential proarrhythmic effects (95). The benefit of these antidepressants is still unclear; results of clinical trials are pending.

Development of Heart Failure During the development of heart failure, a complex network of compensatory mechanisms is activated on macro- and

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microstructural, cellular, and molecular levels to maintain heart function. The most important parts of this network include the stretch-induced increase of the cardiac preload by the Frank-Starling mechanism, activation of different neurohormonal pathways, and structural changes in the myocardial architecture. Independently of the underlying cause, a conserved compensatory pattern occurs in heart failure. These mechanisms are, however, influenced by several, noncontrollable factors such as age, gender, or genetic background. The compensatory mechanisms and the results of their exhaustion are listed in Table 5.

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Table 6 Shift along the Frank-Starling Curve and Its Causes Right

Left

Isolated

–

Treatment with positive inotrope

Isolated diastolic dysfunction

Downward Depressed contractility

–

Decreased contractility increased afterload

Isolated

Increased cardiac performance

–

Upward

Basic concepts At the end of diastolic ventricular filling, myocytes reach their maximal stretch length, which is determined by myocardial compliance, the filling volume, and the resting force. The distending force or filling volume, which occurs in this status, is the preload. Preload can be calculated as: preload = (LVEDP×LVEDR)/2h, where LVEDP is the left ventricular end-diastolic pressure, LVEDR means left ventricular enddiastolic radius and “h” represents the left ventricular thickness. During ventricular contraction and transmission of the stroke volume (SV) into the systemic circulation, left ventricular EF is determined by resistance and capacity of the peripheral vasculature. It is called the afterload of the heart. It is, therefore, a consequence of aortic compliance, wave reflection, and small vessel resistance (left ventricular afterload) or similarly pulmonary artery parameters (right ventricular afterload). Left ventricular afterload is increased in arterial hypertension or aortic stenosis, where the left ventricle has to overcome the elevated peripheral resistance and decreased compliance. In contrast, in mitral regurgitation a decreased ventricular afterload occurs. In conclusion, the three determinants of left ventricular function are myocardial contractility, preload, and afterload. In heart failure, they can also lead to adaptive compensation or further progression. The most important mechanisms influencing these factors are the Frank-Starling mechanism and Laplace’s law.

Frank-Starling mechanism The relation between left ventricular pressure and volume is presented in the Frank-Starling curve. It shows that the major three parameters of cardiac function are venous filling determining left ventricular end-diastolic volume (preload), peripheral resistance (or afterload), and myocardial contractility. The ability of the heart to change its contraction force and increase SV due to an elevated preload, is called FrankStarling mechanism. It describes the length (sarcolemma)tension (stretching)-force (contractility)-velocity (SV) relation in the heart (42). In which way the myocyte sarcolemma elongates, is still unclear, but there are some theories like the length-dependent reduction in lateral spacing between thick and thin filaments, or calcium-induced cross-bridge attachment and detachment. There is no single Frank-Starling curve,

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which explains the pathophysiologic adaptation of the ventricle. There is actually a shift along the standard curve, which is defined by the afterload and inotropic state of the heart. A plateau in the Frank-Starling curve may also develop in certain cases, if the heart simply reaches its maximum capacity to increase its contractility in response to increasing stretch. The plateau in the Frank-Starling curve also represents a reduction in the heart’s systolic reserve. The changes, shifts in the Frank-Starling curve and their causes are represented in Table 6.

Laplace’s law/Young-Laplace equation LV wall stress = (LV pressure × radius)∕2xLV wall thickness The Young-Laplace equation describes the capillary pressure difference between two static fluids due to surface/or wall tension. In cardiac physiology, the equation defines the factors that have an effect on ventricular wall stress. It has a great importance in evaluating the actual oxygen demand of the heart, which is directly proportional to wall stress.

Causes for an elevated ventricular wall stress and therefore increased oxygen demand

. Elevated afterload (increased left ventricular pressure) . Arterial hypertension . Aortic valve stenosis . Systolic heart failure with left ventricular dilation (increased left ventricular radius)

. Valvular heart diseases . Cardiomyopathies . Increased left ventricular wall thickness . Chronic hypertension . Aortic valve stenosis . Hypertrophic obstructive cardiomyopathy

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Pathophysiology of Heart Failure

Pressure-volume loop

LV pressure (mmHg)

160 Normal Decreased afterload Increased afterload Increased inotropy Decreased inotropy

80

0 0

ESV

100

EDV

200

LV volume (mL)

Figure 1 PV loop showing the correlation of pressure and volume alterations in physiological and pathological conditions.

. Decreased left ventricular wall thickness . Myocardial infarction Pressure-volume loop The Frank-Starling curve does not show the influence of venous return on end-diastolic and end-systolic volume. Therefore ventricular function should be described in terms of pressure-volume (PV) diagrams. The PV curve represents the pressure and volume changes during the heart cycle. For instance, when the venous return increases, the diastolic filling of the ventricle elevates the ventricle’s passive pressure, leading to an increased end-diastolic volume. If the ventricle contracts with this preload and constant afterload, the ventricle will empty to the same end-systolic volume, thereby increasing its SV. Afterload alterations as well as valve dysfunctions can also be presented in the PV curve. Alterations in cardiac inotropy and afterload with their hemodynamic effects are shown in Figure 1. For the complete and clear understanding of the PV loops, the following hemodynamic parameters should be defined: Stroke volume (SV): SV is the ejected blood volume from the right/left ventricle in a single contraction. It can also be defined as the difference between the end-diastolic and the end-systolic volume. Ejection fraction (EF): EF is the fraction of end-diastolic volume that is ejected out of the ventricle during each contraction. Cardiac output (CO): CO is defined as the amount of blood pumped by the ventricle per defined unit time. Stroke work (SW): The ventricular SW represents the work performed by the left/right ventricle to eject the SV into the

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connected vessel, the aorta, or pulmonary artery, respectively. dP/dtmin and dP/dtmax: These parameters define the minimum and maximum rate of ventricular pressure changes. Tau: Tau shows the exponential decay of pressure during isovolumetric relaxation in the ventricles. Calculation of Tau is performed by the Glantz method: P(t)= P0e-t/τE + Pα, where P defines pressure at time point “t,” P0 shows amplitude constant, τE is the Glantz relaxation constant, and Pα means non zero asymptote. Arterial elastance (Ea): Ea represents the arterial load and is defined as the ratio of ventricular end-systolic pressure and SV. End-systolic pressure volume relationship (ESPVR): ESPVR represents the maximal pressure at a given volume that can be reached by the ventricle. The slope of ESPVR represents the end-systolic elastance, which is an index of myocardial contractility. It becomes steeper and shifts to the left as contractility increases and becomes flatter and shifts to the right as inotropy decreases, respectively. End-diastolic pressure volume relationship (EDPVR): EDPVR describes the passive ventricular filling curve. The slope of the EDPVR defines the ventricular stiffness. Pressure-volume area (PVA): PVA shows the total ventricular contraction energy.

Remodeling in heart failure The term remodeling is used to summarize the structural and subsequent functional changes in the heart after injury. It

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subsumes alterations in heart dimensions, mass, and shape in response to a specific cardiac event (41, 61). Remodeling can be divided into physiologic/pathologic or adaptive/maladaptive. Physiologic remodeling is called “athlete’s heart” (78), when the remodeling occurs after physiological stimuli. It is clearly different to pathologic remodeling. For example, there is no pathologic fibrosis. The molecular mechanisms are unclear but might involve IGF signaling. Pathological remodeling develops if the underlying cause is a pathological process, for example, cardiac injury, pressure, or volume overload. Independently of the underlying pathologic cause, cardiac remodeling has a common molecular, biochemical, mechanical pathway, and involves all cells and components of the entire heart: cardiomyocytes, fibroblasts, endothelium, and the interstitium (58). There are several modifying factors that have an effect on cardiac remodeling, such as activation of the neurohumoral system, blood pressure, or the hemodynamic changes in heart chambers. The main macrostructural characteristics of cardiac remodeling are ventricular hypertrophy and dilation due to cardiomyocyte reorganization and elongation, increased ventricle wall tension, and impaired subendocardial perfusion. Cardiac remodeling is accompanied by several cellular changes, such as cardiomyocyte hypertrophy, myocyte apoptosis and necrosis, fibroblast proliferation, accumulation of proinflammatory mediators, and extracellular matrix reorganization characterized by fibrosis induction. Progression of cardiac remodeling is influenced by many factors, including the severity of the causing event, possible secondary events, adaptive compensating mechanisms, adverse reactions, and the efficacy of the treatment. There is no exact time point when the transition from possible adaptive to maladaptive remodeling occurs or how this could be identified (Table 7).

Table 7 Summary of Cardiac and Vascular Architectural and Functional Changes

Cardiac

Architectural

Functional

Ventricular dilation

Decreased SV and CO

Ventricular hypertrophy

Increased end-diastolic pressure

Increased ventricular stiffness

Impaired filling (diastolic dysfunction) Reduced EF (systolic dysfunction)

Vascular

Constriction of arteriolar resistance vessels

Impaired organ perfusion

Increased systemic vascular resistance

Increased afterload

Increased venous pressure

Increased preload

Decreased venous compliance

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Reverse remodeling The term left ventricular reverse remodeling (LVRR) refers to the improvement of the cardiac function after the complete development of heart failure, due to compensatory mechanisms (101). It describes a broad spectrum of beneficial physiological alterations in the heart resulting in myocardial recovery. Structurally it is defined by reduced ventricular chamber volumes and pronounced sphericity. It is characterized by an improved β-adrenergic sensitivity and therefore by better heart-rate responsiveness. Furthermore, it is associated with a decline in inflammatory mediators, such as IL-1, IL-8, or TNFα. On a molecular level, reverse remodeling impacts on myocyte size, function, excitation-contraction coupling, bioenergetics, and a host of molecular pathways that regulate contraction, cell survival, mitochondrial function, oxidative stress, and several other features. Reverse remodeling has already successfully been achieved by pharmacotherapy such as by renin-angiotensin-aldosterone system (RAAS) inhibitors or β-blockers, and by interventional-surgical therapy approaches like cardiac resynchronization therapy or the implantation of left- or biventricular assist devices (5, 115). There are numerous clinical and imaging factors, which can predict LVRR, inter alia 2D-echocardiographic parameters, such as left ventricular end-systolic volume or strain imaging, which is able to identify global and regional left ventricular function, scar burden, or myocardial viability (21, 97).

Architectural changes in heart failure Microstructural changes Cardiomyocyte hypertrophy, apoptosis, and necrosis The first and most important responses to chronic pressure and/or volume overload of the heart include hypertrophy of cardiomyocytes, accelerated apoptosis-regeneration circle of cells and remodeling of the myocardial structure. Myocardial injury sets into motion several signaling pathways on the molecular level resulting in adaptive reactions. Due to the activation of the neurohormonal cascades, vasoactive components (angiotensin II, endothelin-1, or vasopressin) are released. The following vasoconstriction increases the cellular calcium concentration in cardiomyocytes via calcium preload, afterload, and the induction of cyclic adenosine monophosphate (cAMP) formation. The increased intracellular calcium level has a positive inotrope and a negative lusitrope effect, thus improves cardiac contractility and decreases myocardial relaxation. However, an excessive calcium entry into the cells and the increased cardiac contractility often leads to malignant arrhythmias and—in extreme cases—to sudden cardiac death (17). The shift to myocyte apoptosis in the strictly balanced cell turnover (125) causes first a scattered, later a diffuse loss of cardiomyocytes (124). As a consequence of the slower turnover and maladaptive reactions of the cardiomyocytes, the presenting pressure and/or volume overload affects the remaining intact myocytes

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and therefore puts greater pressure on them. It also concerns the myocyte progenitor cells, leading to an impaired turnover (3, 62). This processes result in decreased ventricular contractile function and eventually in heart failure over time. Cardiomyocyte apoptosis and necrosis occurs predominantly in postinfarction heart failure, but presents in all other forms of heart failure as well.

Interstitial fibrosis The cardiac interstitium is made up of three different components: the endomysium, the perimysium, and the epimysium. The endomysium surrounds single cardiomyocytes, the perimysium groups of myocytes, and the epimysium envelops the chambers of the heart. It gives a basic framework for cellular components, maintains normal tissue tensile strength and stiffness, and transmits the myocyte-generated contractile force. Furthermore, it also plays part in myocardial homeostasis by providing a surface for different processes, such as cell migration, differentiation, proliferation, or signaling pathways. It regulates fibroblast metabolism and turnover (39, 130). Heart failure is accompanied by the progressive accumulation of interstitial collagen fibers, which decrease the myocardial contractility and compliance, and therefore cause ventricular systolic and/or diastolic dysfunction (106). The exact mechanism of these fibrotic changes is still unclear, but there are two main theories. First, it is thought that a reactive collagen fiber accumulation occurs in the interstitium and perivascular regions and leads to fibrotic changes. On the other hand, an adaptive, reparative fibrosis due to myocyte loss is suspected. Not only the amount of the cardiac collagen changes in heart failure, but also the quality with a shift from insoluble to soluble collagen, leading to reduced myocardial cross-linking and therefore an impaired ventricular contraction. The formed fibrotic tissue is a dynamic structure, metabolically active, contractile, and is able to adapt to changing circumstances. Due to interstitial fibrosis, the capillary density also reduces, which results in an impaired oxygen supply of the tissues and therefore hypoxia-induced structural changes and apoptosis/necrosis of the cells. Collagen turnover of the heart is regulated by several factors. Collagen synthesis is induced by growth factors, like TGFβ (67), PDGF, FGF, by different cytokines, such as IL-1, IL-4 (54), tumor necrosis factor α (TNFα) and also by hormones and some different regulating factors like aldosterone, angiotensin II (131), or endothelin. The degradation of the extracellular matrix collagens is controlled by matrix metalloproteinases (MMPs). The main function of MMPs is the support of tissue remodeling, which occurs in several physiological (morphogenesis) and also pathological (metastasis) conditions. In the heart, they present under physiological conditions in an inactive form in the ventricle, and become activated after myocardial injury. The activation of the MMPs leads to collagen degradation and thereby increased chamber dimensions and reduced SV (34). For instance, MMP-9

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is thought to be the mediator of cardiac remodeling after myocardial infarction (48). MMP-9 deleted mice had less collagen accumulation and fibrosis and less ventricular dilation after myocardial infarction (35). Not only MMPs, but their inhibitors play an important role in heart failure. The most dominant and specific inhibitors are the family of tissue inhibitors of metalloproteinases (TIMP 1-4). The extracellular matrix is a dynamically changing, reorganizing, “living system” with a constant turnover of its components. The balance of MMPs and the TIMPs maintain the homeostasis of the interstitial architecture.

Macrostructural changes

Left ventricular hypertrophy The primary architectural characteristics of cardiac remodeling are the measures of left ventricular mass, volume, and their interrelationship, resulting from the cardiomyocyte reorganization pattern (69). A classification system involving these parameters has been established by the American Heart Association. It defines cardiac remodeling on the basis of M-mode echocardiographic measurements as an elevated left ventricle mass >115 g/m2 in men and >95 g/m2 in women, or as a relative wall thickness (RWT) of >0.42. From this categorization, three different macrostructural responses to cardiac injury can be defined: concentric (increased LV mass, increased RWT), eccentric (increased LV mass, normal RWT), and combined concentriceccentric hypertrophy (23, 31). Eccentric hypertrophy can be further divided into three different subtypes according to the origin of the structural reorganization (Fig. 2). Concentric hypertrophy occurs after pressure overload of the heart, for example, by arterial hypertension or aortic stenosis. It presents with or without an increase of the myocardial mass and is characterized by increased wall thickness with parallel organized sarcomeres and myocyte thickening. The diastolic PV curve shifts to the left along the volume axis. Furthermore, the ventricular diastolic pressure elevates without a significant increase in the ventricle stiffness. Eccentric hypertrophy due to physiological stimulus/athlete’s heart syndrome/AHS is a physiological adaptive condition presenting in young sportsmen—commonly in endurance athletes—with relevant sinus bradycardia, exercise-induced cardiomegaly, and eccentric cardiac hypertrophy with increased CO. AHS is generally considered benign, it does not affect the overall survival, but it is crucially important to differentiate it from hypertrophic cardiomyopathy, a genetic heart disorder, which is a leading cause of sudden cardiac death in young athletes (77, 79). Eccentric ventricle structure reorganization after volume overload (e.g., severe mitral regurge) results in increased cardiac mass and chamber volume. The changes in ventricle wall thickness depend on the mechanism; it can be normal, increased, and decreased as well. Sarcomeres are organized in longitudinal series. Over time, wall-thinning develops and the heart geometry takes up a more spherical shape, associated to a continuous decline in left ventricular EF.

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Normal

Physiological state

Physiological myocardial mass, diameter, wall thickness

Concentric

Arterial hypertension Aortic stenosis

Increased wall thickness Normal/ increased myocardial mass Parallel organized sarcomeres

Eccentric

Mitral valve regurge Dilative cardiomyopathy

Increased mass Increased chamber volume Wall thinning Longitudinal organized sarcomeres

Combined

Myocardial infarction

Dilation in nonfunctioning areas Hypertrophy in functioning areas

Figure 2 Macro- and microstructural changes in eccentric, concentric, and combined remodeling.

Eccentric hypertrophy by dilated cardiomyopathy (20) results from a specific damage to the myocardium, which occur by metabolic, infectious, or toxic agents. The deterioration of the cardiac function is more rapid than in any other forms of eccentric hypertrophy, caused by frequent concomitant regional wall motion abnormalities and heart valve dysfunction. Combined concentric/eccentric left ventricle remodeling presents, for example, after myocardial infarction. Due to the infarcted, fibrotic tissue, dilation develops in the nonfunctioning area, and increased pressure occurs in the functioning areas and causes concentric hypertrophic changes.

Ventricular dilation Ventricular dilation may occur in response to three different cardiac injuries: hypervolemia by impaired renal or cardiac function, volume overload, for example, by aortic or mitral regurgitation, or in dilated cardiomyopathy (idiopathic, alcoholic, etc.). In ventricle dilation, new myocardial sarcomeres are added sequentially to preexisting sarcomeres. The modified structure first increases the ventricular compliance, but over time the ventricular wall stress rises, and impaired oxygen supply occurs. The heart’s mechanical and functional

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efficiency becomes impaired, and leads to heart failure. Not only the ventricles but the atria may also respond with chamber dilation to chronic volume overload (e.g., in mitral valve regurge). In conclusion, a more spherical shape of the heart by progressive dilation generates numerous pathological, structural alterations, such as mitral insufficiency with regurgitation by pulled-away papillary muscles.

Left ventricular stiffness, compliance Left ventricular stiffness is defined by the relationship between ventricular pressure and volume, as the passive change in volume divided by the associated change in pressure (135). Increased left ventricle stiffness occurs as result of many influencing factors, such as elevated filling pressure, decreased distensibility, and steeper curve of the ventricular PV ratio (110, 133). A rise in filling pressure occurs under pathological conditions such as volume overload secondary to acute valvular regurgitation. Decreased distensibility is characteristic in extrinsic compression of the ventricles. A shift to a steeper curve of the ventricular PV ratio results most commonly from increased ventricular mass and wall thickness, for example, in aortic stenosis, or hypertension, and also from infiltrative disorders, for example, amyloidosis (40).

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Ventricular compliance is the ability of the heart chamber to distend and elevate the transmural pressure to increase its volume.

Pathophysiology of Heart Failure

Table 8 Biomarkers in Heart Failure Neurohormones

Norepinephrine (NE) Renin Angiotensin II (AT-II)

Activation of the Neurohumoral System The first activated system in response to impaired cardiac function is the neurohumoral system, which includes the sympathetic nervous system, the RAAS and vasoactive peptides. In heart failure, the pressure-baroreceptors are activated in the carotid sinus, aortic arch, and in the left ventricle. The afferent signals modify the central cardioregulatory centers to increase the circulating blood volume. Sympathetic and humoral efferent mechanisms are stimulated, and the antidiuretic hormone arginine vasopressin is released from the posterior pituitary gland. Sympathetic activation of peripheral organs, for example, kidney, vasculature, skeletal muscles, or the heart itself results in perfusion redistribution. Furthermore, constant neurohumoral activation leads to transcriptional and posttranscriptional changes in the genome, especially by genes regulating the structure and mechanics of cardiomyocytes. There are also several biomarkers involved in the adaptive processes, listed in Table 8.

Aldosterone Arginine vasopressin/ADH ET-1 Myocyte strain specific molecules

Natriuretic peptides: BNP, NT pro-BNP, ANP Adrenomedullin Cotransport inhibitory factor (CIF) Growth-differentiation factor-15 (GDF-15) ST2 Apelin Bradykinin Urotensin II

Cardiac injury induced peptides

Cardiac Troponins: Troponin T, Troponin I Creatine kinase with/without MB-fraction (CK+/-MB) Myosin light-chain kinase I

Sympathetic nervous system The activation of the systemic and cardiac sympathetic nervous system is the fastest adaptive response mechanism in heart failure (65). The sympathetic nervous system is activated by pressure-sensitive (baro-) receptors. Under physiological circumstances, “high-pressure” baroreceptors in the carotid sinus and aortic arch, and “low-pressure” baroreceptors, located in the walls of major veins and in the right atrium of the heart, are the main inhibitors of the sympathetic nervous system. In contrast, the peripheral chemoreceptors activate the sympathetic nervous system. The cooperation of these two systems results in low sympathetic activity and high heart rate variability, according to the actual needs. In heart failure, this precisely controlled balance shifts: the baroreceptor inhibition decreases and excitatory impulses increase. This generalized sympathetic activation with concomitant parasympathetic decrease is followed by impaired heart rate variability, elevated blood pressure, and increased peripheral resistance. It results in a positive inotropic (increased contractility) and chronotropic (tachycardia) effect, which cause blood redistribution by peripheral vasoconstriction and central vasodilation to maintain the perfusion of vital organs. It activates the RAAS that controls the salt-fluid homeostasis and arterial blood tension. The plasma noradrenalin level rises, which correlates with mortality in patients with advanced heart failure (111). However, in severe heart failure, the plasma noradrenaline level and myocardial tyrosine-hydroxylase decrease significantly, possibly due to exhaustion after prolonged activation in the course of the disease. Besides β1-adrenergic activation, the myocardial

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Heart-type fatty-acid protein Proinflammatory mediators

CRP Cytokines: TNFα, IL-6 Chemokines: MCP-2, IL-8, NAP-2, GRO-α Fas (APO-1)

Oxidative stress components

Myeloperoxidase Xanthine oxidase and uric acid Allantoin Oxidized LDL

α1-receptors will also be stimulated with the result of an increased peripheral vascular tone and positive inotropy (52, 91). The sympathetic activation has some negative effects as well: the release of catecholamines can potentiate different arrhythmias and may aggravate myocardial ischemia. Furthermore, plasma epinephrines are also well-known directly toxic to cardiac myocytes and induce their hypertrophy and apoptosis as well. Moreover, norepinephrine causes different signal-transduction abnormalities, like the downregulation of β1- or uncoupling of β2-adrenergic receptors. The activation of the β1-receptors cannot only induce reflectory tachycardia but malignant ventricular arrhythmias too. The maladaptive systemic and regional vasoconstriction leads further to different organ failures, such as renal failure, pulmonary hypertension, etc. The decreased

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Table 9

Comprehensive Physiology

Biological Effects of Activated Cardiac Adrenergic Receptors

Adrenergic receptor

Beneficial effect

Harmful effect

α1c

Positive inotropy

Myocyte damage Proarrhythmic Vasoconstriction

β1

Positive inotropy

Myocyte damage, apoptosis

Positive chronotropy

Fetal gene induction

Vasodilation (epicardial)

Proarrhythmic

Positive lusitropy β2

Positive inotropy

Proarrhythmic

Positive chronotropy

Fibroblast hyperplasia

Vasodilation (small vessel) Antiapoptotic Positive lusitropy

activity of the parasympathetic nervous system results in abnormal autonomic modulation and reduced heart rate variability. The activation of the sympathetic nervous system can have beneficial effects by the adaptation to altered physiological circumstances but may also be harmful. (Listed in Table 9.) Beta-adrenergic signaling pathways play a pivotal role in cardiac function and dysfunction (73). Cardiomyocytes express all β-adrenergic receptor subtypes; β-receptors are also expressed in nonmyocyte cells [endothelial cells and fibroblasts (60)]. In heart failure, the sympathetic signaling pathways are activated and cardiac beta receptor number, density, and activity are reduced with decreased catecholamine sensitivity (22) Gsα and adenylyl-cyclase (51) become downregulated, which are part of rate limiting steps in the signaling pathway. These alterations can be interpreted as compensatory protecting effects, which save the cardiac reserves by protecting from arrhythmias, apoptosis, and cardiac hypertrophy; however, they may also lead to functional deterioration by energy starvation. Further contributing factors are the GRKs (15), which are significantly upregulated and activated in heart failure (123, 138) Figure 3 shows beta receptor signaling pathways in the heart with modulated targets and functional effects.

β2AR

β1AR

AC Ca2+

Gi

Gs

Gs

Ca2+

ATP cAMP SERCA

p PKA

Ph p

P13K

PLA2

Src

CREB

Troponin I

RyR

CaMKII

Ras Akt

Raf MAPKK

Apoptosis

Inotropy

Hypertrophy

Lusitropy

Inotropy

Apoptosis

Figure 3 Beta-adrenergic signaling pathways and their effects in the heart.

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Renin-angiotensin-aldosterone system activation The activation of the RAAS is pressure-mediated reflex, which potentiates the prorenin-renin conversion and renin release from the macula densa in the juxtaglomerular cells of the kidney. The macula densa is made up of granular cells, modified pericytes, which lie in the glomerular capillaries and can release renin into the blood. The plasma renin stimulates the transformation of the inactive dekapeptide prehormone angiotensinogen to angiotensin I by cleaving four amino acids. The octapeptide angiotensin I is then converted into angiotensin II by angiotensin-converting enzyme, released mainly from the pulmonary capillaries. Angiotensin II is a vasoactive agent, causing vasoconstriction, blood pressure elevation, myocyte hypertrophy, myocyte cell death, myocardial fibrosis, and stimulates the secretion of aldosterone from the adrenal cortex. The angiotensin II receptors are mostly found on the intraglomerular mesangial cells, causing them to contract and stimulating the adrenal cortex to release aldosterone. Aldosterone is a hormone, released from the zona glomerulosa; its main effect is to increase the sodium and water reabsorption from the kidneys into the blood. Angiotensin II cannot only be synthesized by the RAAS, but also through an independent pathway through a conversion by kallikrein and cathepsin G, or in the tissue through chymase activation (11).

Effects of angiotensin II The major bioactive molecule of the RAAS system with endocrine, autocrine, paracrine, and intracrine effects is angiotensin II. It has various effects in the whole body and induces several pathways to regulate tension and sodiumfluid regulation. Angiotensin II is a general vasoconstrictor in all arterioles with a marked effect on the renal efferent arterioles. It stimulates the release of aldosterone, induces the excretion of noradrenalin from the sympathetic nerve terminals (33), and inhibits the vagal tone. As a result, the intraglomerular pressure and glomerular filtration rises, which results in decreased hydrostatic and increased oncotic pressure, and therefore an induced sodium and fluid reabsorption into the peritubular capillaries. Sodium reabsorption occurs eventually due to active and passive mechanisms. First, the decreased perfusion of the vasa recta leads to decreased sodium washout. Increased fluid reabsorption by peritubular capillaries increases the passive reabsorption of sodium. Moreover, the Na+/ H+-exchangers of the proximal tubules and the thick ascending region of Henle-loop are stimulated by angiotensin II and reabsorb sodium. Finally, the hypertrophy of other renal tubular cells through angiotensin II leads to sodium reabsorption. Angiotensin II is not only a vasoactive hormone, it has also been shown that cardiac angiotensin II has local positive inotropic, negative lusitropic effect on the heart, and increases the afterload that elevates further the energy expenditures of the heart. Angiotensin II has also a direct effect on cardiomyocytes: it promotes hypertrophy, myocyte

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apoptosis, and causes structural and biochemical alterations in the extracellular matrix (81, 140). Angiotensin has furthermore metabolic effects, such as upregulation of tissue lipogenesis and reduction of lipolysis, and thereby causes fat mass expansion in the body. Moreover, the induced RAAS often leads to secondary hyperaldosteronismus (30). The effects of angiotensin II and its further metabolization are shown in Figure 4.

Further metabolization Angiotensin II may undergo further cleavage producing angiotensin III [Ang-(2-8)], IV [Ang-(3-8)], and angiotensin (1-7). Angiotensin III is produced by aminopeptidase A, a zinc-dependent, membrane-bound enzyme, by cleaving the N-terminal acidic aspartate amino acid (103). Angiotensin III has lower pressure effect than angiotensin II, but induces aldosterone-production the same way and mass. Angiotensin IV is a product of the cleavage of angiotensin III by aminopeptidase N that releases neutral amino acids from the N-terminal region. The hexapeptide angiotensin IV has also moderate angiotensin II-like effect. Angiotensin (1-7) is a heptapeptide product of angiotensin II or I by endo- and carboxypeptidases, respectively. Its effects counterweigh the vasoactive impact of angiotensin II by reversing the pathological processes including fibrosis and inflammation. Angiotensin (1-7) influences tissue metabolism by increasing the glucose uptake and lipolysis, and parallel decreasing insulin resistance and dyslipidemia. It inhibits cell proliferation and angiogenesis; therefore it is thought to be a promising target for cancer therapy.

Receptors The two major—G-protein receptor associated—receptors that mediate the effects of angiotensin II are the angiotensin type-1 receptor (AT1R) and the angiotensin type-2 receptor (AT2R) (122). AT1R is expressed mainly in the vasculature, kidney, adrenal cortex, lungs, and in the brain, whereas AT2R is located rather in the myocardium, and more usual in the fetus and neonate (57). In the myocardium, AT1R is found in nerves, but AT2R rather in fibroblasts and in the extracellular matrix. The effects mediated by AT1R include vasoconstriction (due to the activation of the PLC signaling pathway) with vascular smooth muscle cell proliferation, cell growth, aldosterone synthesis and secretion, vasopressin secretion, and catecholamine release. It leads to decreased renal blood flow and renal renin inhibition as a negative feedback. AT2R activation results in vasodilation, natriuresis, and bradykinin release. It inhibits cell growth and differentiation. There are also other, still incomplete characterized subtypes of angiotensin receptors, namely, the AT3 and AT4 receptors (26). The distribution and functions of the angiotensin receptors AT1R and AT2R are listed in Table 10.

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Angiotensinogen Renin Angiotensin I ACE Angiotensin 1-7

Angiotensin II

ACE 2 Further metabolization

Effects

APA Angiotensin III APN Angiotensin IV

AT1

AT3+AT4

AT2

Vascoconstriction NO Hypertrophy Antiproliferation Proliferation Vasodilation Anti-inflammation ↑ Na+ retention Antioxidative ↑ Oxidation Inflammation Thrombosis

Adrenal

Laminin ↓PAI-1 ↑ NO ↓ ET ↓ TIMP-1

Aldosterone

Heart

Kidney

Interst Fibrosy

Salt and fluid retention K+ secretion

Heart Failure

Congestion, electrolyte imbalance

Other effects (endothelial dysfunction, platelet aggregation, etc.)

Figure 4 Major effects and further metabolization of angiotensin II.

ADH/antidiuretic hormone/arginine vasopressin The plasma concentration of the antidiuretic hormone or vasopressin is significantly elevated in heart failure and even more pronounced in patients receiving an antidiuretic therapy (105). The increased release of vasopressin occurs due to stimulation of the carotid sinus and aortic arch baroreceptors. It contributes to increased afterload and volume overload due to fluid retention by increased intake and reabsorption from the collecting tubules (44). The combination of decreased water excretion and increased water intake often leads to fall of plasma sodium concentration. Clinical hyponatremia represents an important prognostic factor in heart failure. Vasopressin acts on three different G-protein-coupled receptor subtypes, V1A, V1B, and V2 (18). The V1A receptor is found on vascular smooth muscle cells and cardiomyocytes. These receptors activate the inositol triphosphate pathway and cause increased intracellular calcium concentration. The activated calcium signaling results in vasoconstriction, increased systemic vascular resistance, and positive inotropy, but leads to reverse remodeling and progressive heart failure by sustained activation. Moreover, it also potentiates the synthesis of contractile proteins in myocytes. The renal effects of vasopressin, such as the upregulation of the aquaporin-2 water channels, are mediated mainly by the V2 receptor. Chronic volume

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overload by activated V2 receptors contribute to ventricular remodeling and dysfunction by exacerbating the diastolic wall stress.

Natriuretic peptides As a mild cardiac dysfunction develops to congestive heart failure, a relative imbalance occurs in the endogenous vasoconstrictor-vasodilator regulation of the vessels, for the benefit of vasoconstriction. The concentration of the vasodilative nitric oxide, bradykinin, and natriuretic peptides declines, whereas vasoconstrictive agents increase their plasma concentrations. Natriuretic peptides are endogenous peptide hormones, which are released from the heart chambers as a response of cardiomyocytes to myocardial stretch due to volume or pressure overload. They promote vasodilation and natriuresis, so the atrial/ventricular filling decreases, and the subsequent reduction in preload reverses, or at least slows down cardiac remodeling. Additionally, BNP (brain natriuretic peptide) inhibits the RAAS (104) and the adrenergic activation. As important members of the compensatory mechanisms in heart failure, the concentration of natriuretic peptides has both diagnostic and prognostic relevance (59, 75). Plasma ANP (atrial natriuretic peptide) levels rise in the

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Comprehensive Physiology

Table 10

Distribution

Pathophysiology of Heart Failure

Distribution and Function of the AT1R and AT2R AT1R

AT2R

Adrenals

Adrenals

Blood vessels

Uterus

Brain

Brain

Kidney

Kidney

Heart (nerves) Liver

Table 11 Natriuretic Peptide Concentrations in Different Conditions Elevated plasma natriuretic peptides

Low plasma natriuretic peptides

Ischemic heart diseases

Pulmonary edema

Cardiomyopathies

Acute mitral regurgitation

Heart (fibroblasts, interstitium)

Hypertensive heart disease

Mitral stenosis

Fetal, neonatal tissues

Hyperthyreosis

Left cardiac tumors

Cardiac amyloidosis

Constrictive pericarditis

Peri-/myocarditis

Cardiac tamponade

Conditions with heart failure

Lung Prostate Function

Vasoconstriction

Vasodilation

Cell growth, proliferation

Antiproliferation, apoptosis

Elevated heart rate

Differentiation, development

Increased contractility

Antidiuresis

Increased renal tubular reabsorption

Renal Na+ excretion

Increased aldosterone release

Dilation of the afferent arteriole

Sympathetic hyperactivity

Increased renin release

Increased vasopressin release

Increased NO release

ACTH release

Bradykinin production

Obesity Conditions without heart failure

Advanced age

Pulmonary hypertension

Acute coronary syndrome

Aortic aneurysm

Acute pulmonary embolism Acute respiratory distress syndrome High-output states Renal failure Atrial tachyarrhythmia

targets involve pro- and anti-inflammatory cytokines, endotoxins, adhesion molecules, and chemokines (13). early phase of the development of heart failure, therefore, they have been used as marker for the diagnosis of asymptomatic left ventricular dysfunction (80). Dysregulation of the natriuretic peptide system is associated with several cardiovascular and noncardiovascular diseases with and without heart failure, summarized in Table 11. The biological effects of natriuretic peptides are mediated by membranebound natriuretic peptide receptors, NPRs. They activate a cyclic guanosine monophosphate-dependent signaling pathway, which results in vasodilation, increased diuresis with natriuresis, and hypotension. Both of them inhibit the RAAS, endothelin secretion, and the systemic sympathetic activation.

Immunomodulation The activation of the immune system in cardiac remodeling came into focus in the past decade. Activation of the innate immune system by so called “danger signals” is responsible for inflammatory responses in heart failure. Inflammatory cells, mediators and their interactions have been proven to play a crucial role in the development of heart failure. Therefore, novel pharmacotherapeutical

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Cytokines The concentrations of circulating proinflammatory cytokines are significantly increased in heart failure; however, their exact pathophysiological role, clinical significance and use remain still unclear (109). Cytokines are low molecular weight, biologically active proteins, which act in an autocrine or a paracrine manner to modulate cell function. The most important proinflammatory cytokines involved in heart failure are TNFα, interleukin 1 (IL-1), and 6 (IL-6). These are secreted from the myocardium and mononuclear cells.

TNFα TNFα has a controversial, still not completely understood function in heart physiology. It contributes to the development of cardiac dysfunction but is also known for its cardioprotective effects (102). Under physiological conditions, the heart does not produce TNFα, in contrast, after an acute injury the concentration of TNFα raises significantly. Myocyte stretch, ischemia, pressure, or volume overload are thought to potentiate TNFα production as well (37). TNFα was found to increase

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the expression of antioxidant enzyme manganese superoxide dismutase and mitochondrial protein A20, in sense of a protective role in the heart. TNFα is thought to have adverse effects as well, such as a direct toxicity on cardiomyocytes, generation of reactive oxygen intermediates, and thereby the induction of oxidative stress. TNFα is supposed to play a pivotal role in the development of left ventricle dysfunction, remodeling, increased myocyte apoptosis, cardiac cachexia, and endothelial dysfunction as well. There are two different TNFα cell membrane receptors defined so far, TNFR-1 and TNFR-2. TNFR-1 is widely expressed and transmits deleterious effects of TNFα. TNFR-2 is thought to exert the adaptive, protective effect in the heart (32).

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Anti-inflammatory cytokines in heart failure: IL-10/interleukin-10 Interleukin-10 is a protein homodimer, which is produced by monocytes, type 2 T-helper lymphocytes (TH2), mast cells, CD4+CD25+Foxp3+ regulatory T cells, and certain subset of B cells. IL-10 downregulates the production of TNFα (112), IL-1 and -6 and reduces the production and release of NO and other reactive oxygen radicals. In contrast, patients with chronic heart failure and elevated IL-10 and TNFα-level had significant higher mortality (6).

Chemokines

IL-1 is made up of two distinct ligands, IL-1α and IL-1β, which both bind to the IL-1 type I receptor and elicit nearly similar effects. The primary sources of interleukin-1 are the myocardial cells themselves, although fibroblasts were already shown to produce IL-1 too. Significantly increased production and release of IL-1 from fibroblasts were observed in hypoxic states, like acute myocardial ischemia. IL-1 depresses myocardial function in a dose-dependent fashion, synergistic with TNFα. Negative chronotrope and inotrope effects of IL-1 were found in animal experiments both in the whole heart and by isolated cells. Further, IL-1 is involved in myocyte hypertrophy, apoptosis, and cardiac arrhythmogenesis. Anakinra, a known recombinant human IL-1R antagonist, was shown to inhibit apoptosis in experimental murine acute myocardial infarction model (1).

Chemokines are chemotactic cytokines, small glycoproteins, which stimulate leukocyte migration, regulate cytokine production, and may induce reactive oxygen species (ROS) formation as a response to an acute inflammatory event. There are four known chemokine subfamilies, differentiated according to the primary amino acid sequences: CXC, CC, C, and CX3C. The plasma concentration of chemokines increases significantly in heart failure, such as MCP-1α and RANTES (118). There are also neutrophil-specific chemokines, the CXC chemokines, including IL-8, neutrophil activating peptide-2 and GROα, whose elevated level is proportional to the severity of the initiating disease. For instance, it has been proven in animal experiments that the overexpression of myocardial CXCR4 results in enhanced recruitment of inflammatory cells, increases TNFα production, and leads to accelerated apoptosis and cell turnover. Furthermore, overexpressed CXCR4 in mesenchymal stem cells induced effectively neomyoangiogenesis in the infarcted myocardium (141).

Interleukin-6/IL-6

Other proinflammatory mediators: C-reactive protein/CRP

IL-6 is a member of a cytokine family with homologous structure and overlapping biological effects. IL-6 signaling requires the interaction of IL-6R and the membrane-bound gp 130, which makes cells susceptible to IL-6. The activation of the IL-6 receptor complex leads to various signaling pathways, involving different transcription factors, such as STAT1 or STAT3 (49). The circulating levels of IL-6 and gp 130 are increased in congestive heart failure and also correlate with its progression and functional class. IL-6 and other IL-6 related cytokines can induce cardiomyocyte hypertrophy in different cell signaling pathways, including STAT3 transcription factor. Based on experiments with cultured cardiomyocytes, IL-6 cannot act directly on cardiomyocytes; its effects depend on the availability of the soluble IL-6R receptor within the myocardium. IL-6 plays also an important part in the development of myocardial dysfunction and muscle wasting, correlates with the decreased functional status of the patient, and provides prognostic information (136).

The pentameric C-reactive protein (CRP) is synthesized in the liver and responds to acute inflammatory stimuli as an acute phase protein. It binds specifically to microbial polysaccharides, opsonizes ligands for phagocytosis, and induces the classical complement pathway via the C1Q complex (7). According to experimental investigations, an increased serum CRP level presents a deleterious factor in myocardial infarction model: the i.v. injection of human CRP into rats after coronary artery ligation augmented infarct size by approximately 40%, while complement depletion completely abolished this effect (47). Administration of a potent CRP inhibitor, 1,6-bis-(phosphocholine)-hexane, to rats after acute myocardial infarction increases infarct size and cardiac dysfunction, induced by human CRP (98). Clinical investigations also corroborated the hypothesis that CRP is a possible predictor in cardiac dysfunction. The Framingham Heart Study revealed that patients with elevated CRP serum levels (>5 mg/L) express a significantly increased risk of heart

Interleukin-1/IL-1

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failure. Moreover, the Rotterdam study was designed to investigate the relation between lower serum CRP concentrations and clinical outcome of heart failure, and defined CRP as a promising, independently associated predictor (56).

Cellular elements in heart failure Monocyte-macrophage system Circulating inflammatory monocytes and macrophages are among the first leukocytes infiltrating the heart during the early proinflammatory phase after myocardial infarction. They participate in inflammatory and reparative processes, and thereby determine left ventricle remodeling (74). Animal experiments showed that monocytes/macrophages dominate in the cellular infiltration in the first two weeks after myocardial infarction and participate in infarct wound healing (88). The recruitment of the subsets of the monocyte-macrophage system after myocardial infarction also correlates with tissue repair. Furthermore, it could be of therapeutical importance to modulate the timing and intensity of recruitment, or the ratio of subsets in tissue repair after MI. Macrophages are diverse extravascular immune cells, distributed in the whole human body and acting on several cell types. There are two different types of macrophages known, the inflammatory, classical, or M1 macrophages, and the reparative, alternative, or M2 macrophages. The different types of macrophages, derived from circulating monocytes are crucially involved in inflammatory tissue remodeling in heart failure. They possibly interact with the surrounding extracellular matrix cells, cardiac myocytes, and endothelial cells.

Adhesion molecules Adhesion molecules are cell surface receptors, which ensure the binding of leukocytes to each other, to the endothelium, or to the extracellular matrix components. In heart failure, three different adhesion molecule groups have been defined: The immunoglobulin group, including the intracellular adhesion molecules (ICAM-1, -2, and -3) and the vascular cell adhesion molecules (VCAM-1) (9, 120). Integrin heterodimers, which mediate lymphocyte adherence to the vascular endothelium, especially LFA-1 and Gp IIb-IIIa in heart failure. Selectins are single-chain transmembrane glycoproteins, involving three different subsets according to the specific binding object, namely the E-selectins (endothelial), P-selectins (platelet), and L-selectins (leukocytes), respectively. These molecules support the adhesion of leukocytes to the endothelium and extravasation. It was suggested that elevated platelet surface P-selectin indicates increased thrombogenicity and is specific for decompensated heart failure. However it has been shown that platelet abnormalities relate rather to the associated comorbidities and occur in stable heart failure as well, despite of antiplatelet medication usage (29).

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Neutrophils Neutrophils have a paradox role in heart failure due to their dual and contrary functions in inflammatory processes. Neutrophils principally destroy invading microorganisms by secreting toxic chemicals, such as ROS or defensins. However, the mechanisms, with which neutrophils are able to kill microorganisms in inflammation, has also the potential to impair normal tissue structure. After acute injury of the heart, neutrophils are recruited contributing to healing processes and scar formation in the myocardium. It has been shown that intense neutrophil chemotactic activation and LTB4 generation presenting in unstable angina pectoris or myocardial infarction relate to cellular activation in myocardial ischemia (84). Neutrophils are recruited in the infarcted myocardium in the first hours after onset of ischemia and peak after one day.

T-cell subsets Whereas most research focused on the infiltration of innate immune cells, it became recently clear that also adaptive immune cells are involved in the pathophysiology of heart failure. Activation of T-cells occurs mainly in lymph nodes draining the heart. Especially regulatory T-cells seem to be involved in healing after myocardial infarction by influencing the conversion from proinflammatory M1 to pro-healing M2 macrophage (132). In contrast, ablation of B cells improved healing after myocardial infarction (142).

Biochemical Changes in Heart Failure Cardiac contraction and relaxation abnormalities are generally attributed to deleterious changes in numerous cellular processes, for example, metabolic pathways, ion channels and pumps controlling excitation contraction coupling, and contractile proteins. These alterations may present either the primary cause for the impaired cardiac function, or may occur secondary due to pressure or volume overload. They altogether reduce myocardial contractility and slow down relaxation. There are two known biochemical mechanisms resulting in depressed cellular function in the myocardium: energy starvation, which acts by decelerating the biochemical processes and inhibiting cellular interactions, and structural/functional abnormalities in contractile proteins.

Excitation contraction coupling and relaxation Excitation contraction coupling is a physical term, which describes the conversion of an electrical stimulus to a mechanical response. In the myocardium it includes processes, which connect the depolarization of the plasma membrane and the cytosolic release of calcium. This cytosolic calcium transient activates calcium-sensitive, ATP-dependent contractile

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Na+

K+

Na+/Ca2+ exchanger 3×Na+ Ca2+

Ryanodine

Ca2+

Sarcoplasmic reticulum Ca2+

ATPase Ca2+

K+ Na+

Ca2+ -uptake pump

Ca2+ Na+/K+ pump L-type Ca2+ channel

Sarcomere

Ca2+ Troponin complex

Figure 5 Excitation-contraction coupling in physiological and pathological state.

myocardial proteins. With the cleavage of high-energy phosphates, the shortening of these proteins causes synchronized global contraction of the heart (16). An initiating cardiac action potential is generated by the pacemaker cells of the heart and conducted to all cells in the heart via gap junctions. By activating membranous T tubules, Ca2+ is forced to enter the cell matrix via sarcolemmal Ltype calcium channels and in the early phase possibly via sodium-calcium exchanger. The increase in Ca2+ concentration is detected by ryanodine receptors (RYRs) in the membrane of the sarcoplasmic reticulum. RyRs represent a class of cellular calcium channels in various contractile tissues. They are the major cellular mediators of the positive feedback mechanism calcium-induced calcium release (CICR) in cells (36). These receptors are activated by a calcium trigger and release calcium molecules from the sarcoplasmic reticulum. The released calcium molecules bind to Troponin C, which moves to the actin-binding site of the tropomyosin complex and induces conformational change. ATP hydrolyses at this place and myosin heads pull the actin filaments toward themselves and thereby shorten the sarcomere length (see in Fig. 5). Relaxation is also an energy-dependent process, in which calcium is actively transported back to the primary emerging cell organelles (27). Calcium is mainly taken up by the sarcoplasmic reticulum by an ATPase pump (SERCA, sarcoendoplasmic reticulum calcium-ATPase) (99). At the end of the cycle—after intracellular calcium concentration drops— all participants in the excitation contraction coupling return into their steady state, a new ATP binds to the myosin head, displacing ADP and the initial sarcomere length is restored.

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Physiologically, cytosolic calcium concentration is regulated by beta-adrenoreceptor-coupled mechanisms. Betaadrenergic stimulation increases cAMP, which induces protein kinase (to modulate L-type calcium channels to release calcium) or activates the IP3 signal transduction pathway, which can stimulate the release of calcium by the sarcoplasmic reticulum through IP3. Moreover, the betaadrenergic-dependent activation of the cAMP-dependent protein kinase phosphorylates phospholamban, a protein located on the sarcoplasmic reticulum that normally inhibits (72) calcium uptake. This disinhibition of phospholamban leads to an increased rate of calcium uptake. Therefore, betaadrenergic stimulation increases the contractility (positive inotropy), and increases the rate of relaxation (positive lusitropy). In heart failure excitation contraction coupling is impaired in some way (45, 134). It can be impaired by decreased transport of calcium into the cell through L-type calcium channels. Dysfunction or lower amount of the L-type calcium channels play a central role in it; decreased cardiac L-type Ca2+ channel activity induces cardiac hypertrophy and heart failure in mice (46). The calcium sensitivity of Troponin C or the myofilaments can also be reduced. Thus, calcium increase in the surrounding of the troponin complex significantly attenuates excitation contraction coupling. In some forms of diastolic heart failure, the function of the sarcoplasmic ATP-dependent calcium pump is impaired. This defect delays the rate of calcium uptake by the sarcoplasmic reticulum and reduces the rate of relaxation, leading to diastolic dysfunction (86).

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Metabolism in heart failure The heart needs and consumes more energy than any other organ of the human body. To reach this enormous demand, the heart converts chemical energy stored in fatty acids and glucose into mechanical energy. If these mechanisms do not reach the demand of the heart, cardiac malfunction, mechanical failure of the heart occurs (50, 55, 108, 114, 127, 139). The “energy starvation” hypothesis subsumes the altered mechanisms of myocardial energetics, which lead to energy depletion. The metabolic and energy production patterns in the failing heart mimic the patterns in the fetal heart. Cardiac energetics is based on three main mechanisms, namely, the utilization of the components, energy production and transfer of high-energy phosphates to the myofibers. The sources include free fatty acids and glucose, processed by beta-oxidation or glycolysis. The metabolic products than enter the Krebs cycle and the mitochondrial respiratory chain. Here high-energy phosphate ATP is produced by oxidative phosphorylation. ATP is then transported to the myofibrils by the creatine-kinase energy shuttle. In heart failure changes occur in all three components of cardiac energy metabolism: substrate utilization, oxidative phosphorylation, and highenergy phosphate metabolism. Substrate utilization can become limiting for cardiac function in heart failure which may occur as a result of reduced substrate uptake, oxidation, or as a change in the relative contributions of fatty acids (60%-90%) and glucose (10%40%) to ATP synthesis. In early heart failure, most studies showed constant or slightly increased fatty acid utilization and increased glucose utilization; however, in advanced heart failure, both of them decrease but with a constant ratio in cardiac metabolism. In advanced heart failure, the activated sympathetic system enhances insulin resistance, decreases insulin release from the pancreatic beta cells, increases hepatic glucose production through gluconeogenesis and glycogenolysis, and increases glucagon production. Enhanced sympathetic activity and RAAS increase the serum level of free fatty acids by activated lipolysis and thereby inhibits the uptake of glucose in the muscles, and damages the pancreas by cytokines such as TNFα. Therefore, plasma glucose rises and provokes a pancreatic insulin response, which is not adequate to control hyperglycemia. Increased plasma levels of free fatty acids and glucose also predispose to increased hepatic synthesis of triglycerides. Secondly, impaired energy production can reduce cardiac function by providing an insufficient supply of ATP to cardiac myocytes (125, 126). The most important factor that deteriorates high-energy phosphate production and availability is the reduced oxygen supply of cardiomyocytes. Impaired coronary blood flow leads to an imbalance between oxygen and energy demand and supply. The increasingly produced ROS damage the mitochondrial DNA, and because of its poor repair capacity, fragmented mitochondrial DNA accumulates and leads to further impairment of the energy homeostasis (91). Besides the deleterious effects of free radicals, an antibody-mediated

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damage participates in the dysfunction of mitochondria as well. The functional changes and structural abnormalities of the mitochondria are also detectable in end-stage heart failure: the mitochondrial volume becomes decreased, and an increased amount occurs in the failing heart. Thirdly, impaired ATP transfer and utilization may limit contractile function. The phosphocreatine shuttle, which provides ATP for the cells and retransports ADP, depends on reactions catalyzed by creatine phosphokinase, an enzyme that transfers high-energy phosphates to the cytosol and ADP to phosphocreatine. The rate-limiting step in energy production in the heart is the ADP-rephosphorylation and retransport to the mitochondria. Creatine phosphokinase levels are decreased in heart failure, slow rephosphorylation of ADP, and thus play a major role in energy starvation in heart failure. Compensation by isoform switch from M (adult) to B (fetal) is possible, and provides another evidence of the suggested switch to fetal metabolic pattern in heart failure. The allosteric effects of ATP, such as accelerating ion pumps, facilitating ion exchangers, and passive ion fluxes, are also significantly reduced in heart failure. It affects even calcium fluxes, which mediate excitation contraction coupling. The lack of ATP fails to accelerate the calcium flux into the sarcolemma and sarcoplasmic reticulum, which leads to reduced contractility. Relaxation is also involved, as the low availability of ATP fails to stimulate the active transport of calcium out of the cytosol and Na+/Ca2+ exchanger. As side-effect, sodium accumulates, and intracellular potassium decreases, which is arrhythmogenic, because low potassium levels lead to depolarization of the plasma membrane. Reduced free energy by impaired terminal phosphate hydrolysis of ATP plays also a role in energy starvation. Thus there is a cardiac phosphorylation reserve; a small decrease in the phosphorylation activity can impair ATP-dependent reactions.

Oxidative Stress in Heart Failure Several experimental and clinical studies suggest that oxidative stress contributes to the development and progression of heart failure.

Oxidative stress Activated oxidative stress state has been proved in human heart failure: in patients with ischemic and nonischemic heart failure malondialdehyde-like activity, a marker of lipid peroxidation, is increased. There are several other mechanisms and molecules, which have been demonstrated to play an important role in human heart failure, such as biopyrrins (oxidative metabolites of bilirubin), nitrotyrosins (intracellular marker of oxidative stress), or xanthine-oxidase activity. The exact mechanism of oxidative stress impairing cardiac function is not completely understood; however, there are potential molecular processes, which take part in it: the activation of proinflammatory mediators, repetitive

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ROS

MAPK JNK, p38, Akt RyR NF-κβ AP-1

MMPs

DNA damage PARP-1 activation

Nucleus

Sarcoplasmic reticulum Inflammation Apoptosis Necrosis

Contractile dysfunction

Mitochondrium

Fibrosis

Apoptosis

Figure 6 Oxidative stress in heart failure.

ischemic and reperfusion periods, or auto-oxidation of catecholamines. The activation of redox-sensitive signaling pathways (e.g. mitogen-activated protein kinases) and transcription factors (e.g. NF-κB) are implicated in the development of cardiomyocyte hypertrophy (116). Decreased antioxidant activity is also suggested to promote oxidative stress. Additionally, the well-known risk factors for cardiovascular diseases, like hypertension, diabetes, or obesity, are also associated with increased oxidative stress. One possible mechanism, how oxidative stress and reactive metabolites impair cardiac performance is through direct damage of cellular proteins and membranes as well as cellular dysfunction and death. Another mechanism is the potential of ROS to activate MMPs which leads to the reorganization of the extracellular matrix. Oxidative stress mechanisms in heart failure are shown in Figure 6.

Reactive oxygen species High ROS are produced by normal aerobic metabolism. ROS include oxygen-containing free radicals, such as superoxide anion (O2–), hydroxyl radical, and compounds, such as hydrogen peroxide (H2O2). These reactive elements participate in both normal and pathologic biochemical reactions. Superoxide anion is generated intracellularly by the incomplete reduction of O2, by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase or xanthine oxidase (XO), uncoupling of NO synthase (NOS), and electron transport and “leakage” during oxidative phosphorylation in the mitochondria. It can spontaneously or enzymatically lead to hydrogenperoxide (H2O2) production. H2O2 is able to generate the formation of the highly reactive hydroxyl radicals via Fenton

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chemistry under pathological conditions (87). Moreover, at increased levels of oxidative stress, O2− interacts with NO and forms peroxynitrite. Peroxynitrite is potent reactive oxygen derivate, which triggers several cytotoxic processes such as lipid-peroxidation or protein oxidation (38). The altered proteins influence the fine-tuned excitation-contraction coupling and may activate ECM modulating systems like MMPs. They can regulate fibroblast proliferation or collagen synthesis, and are involved not only in MMP activation but also in increased MMP expression. Some potential sources of ROS include proinflammatory cells, mitochondria, xanthine oxidase, and NADPH oxidases. Elevated mitochondrial-derived ROS activation, or induced xanthine-oxidase expression and activity are potential sources of reactive species. Also in clinical studies, patients treated with xanthine-oxidase inhibitor allopurinol after myocardial infarction, had over time lower plasma MMP activity and urinary 8-iso-prostaglandin F2levels, than those in the control group (53). The NADPH oxidases, a group of oxidizing enzymes, are also thought to contribute to ROS generation. Several pathophysiological stimuli involved in chronic heart failure, such as the activation of the neurohumoral system (involving angiotensin II, βadrenergic agonists, endothelin-1, or tumor necrosis factor α) or myocyte stretch can stimulate ROS production by NADPH oxidase induction. Under physiological conditions there is a precisely regulated balance between the production of ROS and the molecules, which are capable of “scavenging” ROS. Experimental animal studies suggest, that oxygen free radicals can exert direct toxicity on the myocardial structure and function. These effects can be reversed by free radical scavengers. For instance, superoxide anion is a potent inhibitor of

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nitric oxide, and the reduced bioavailability of NO contributes to endothelial dysfunction. The Janus-faced NO is able to act against deteriorating oxidative processes by activating several potent antioxidant enzymes, such as xanthine-oxidase or NADPH oxidase. Further, ROS stimulate myocyte growth and ECM remodeling. They activate transcription factors, hypertrophy (Src and PI3K) and apoptosis (p38 and Akt) signaling pathways. ROS also play an important role in G-protein-coupled hypertrophic stimulation by angiotensin II or β-adrenergic stimulation. Reactive species can effectively modulate other, physiological signaling pathways (called “redox signaling”) as well, for example, the induction of the expression of proteins involved in excitation-contraction coupling (such as ion channels, sarcoplasmic reticulum calcium release channels) or myofilament proteins, protein kinases (113) (see table 12). Table 12. Reactive species may also play an important part in both adaptive and maladaptive processes (e.g., the early development of hypertrophy and adverse remodeling respectively). Cesselli et al. have pointed out the link between the induction and modifications in multiple pathways, involved in mediating oxidative metabolism and apoptosis, as well as in the progression of left ventricular dysfunction. Further, the author presents a new signaling molecule, the oxidant

Pathophysiology of Heart Failure

stress-induced, proapoptotic, proto-oncogene p66shc, which definitely links oxidative stress and apoptosis in an experimental pacing-induced heart failure model (25).

Role of the mitochondria in heart failure It is of great interest, if mitochondria, as an important source of ROS are active participants in the development of heart failure. They generate high-energy phosphates by several oxidation-reduction reactions, supported by enzymes forming respiratory complexes. The electron transfer in these respiratory complexes is often followed by an electrochemical gradient by proton transport from the mitochondrial matrix to the inner membrane. This electrochemical proton gradient— or as often called, protonmotive force—provides the energy for the high-energy phosphate formation. If the oxidationreduction processes are incomplete, superoxide and other reactive oxygen-containing species will be generated. Low amount of ROS are built under physiological circumstances as well, but the endogenous antioxidant enzymes, such as superoxide dismutase, manage to eliminate them. In heart failure, the mitochondrial ROS production is augmented, leading to an excessive imbalance in the oxidative-antioxidative processes. Mitochondria contribute to apoptotic processes as well, by

Table 12 Oxidative Modifications of Protein Kinases Rl subunit oxidation

↑ R1 binding to AKAPs (α-MHC) ↑ PKAI kinase activity

32

Catalytic domain Cys199-S-glutathionylation

↓ Kinase activity

34-36

PKG 1α

Oxidation of Cys42 in the homodimerization domain

↑ Affinity for substrates ↑ cGMP-independent catalytic activity

38

PKC

Oxidation of C1 domain Cys residues

↓ Autoinhibition ↑ Kinase activity

59

Calpain-dependent cleavage, release of a constitutively active catalytic domain fragment

↑ PKCα catalytic activity ↑ PKCδ-dependent phosphorylation of 14-3-3

8.85-87

Oxidation of a conserved activation loop Cys

↓ Kinase activity

36, 59

Src-dependent phosphorylation of PKCδ at Tyr311

Altered substrate specificity, acquisition of cTnl-T144 kinase activity

40

PKD

c-Abl- and Src-dependent phosphorylations of PKD at Tyr463 and Tyr95 that relieve autoinhibition, promote PKCδ-dependent PKD phosphorylation at Ser744/Ser743

↑ Kinase activity

50, 51

CaMKII

Met231/Mel282 oxidation

↑ Ca2+-independent catalytic activity

76

ASK-1

Mechanisms that disrupt a C-terminal interaction with 14-3-3: dephosphorylation of Ser967 at the ASK-1 C-terminus or phosphorylation of 14-3-3 by ROS-regulated kinases (PKD. Mst1, catalytic fragment of PKCδ). Mechanisms that disrupt an N-terminal interaction with Trx-1 (Trx-1 oxidation)

↑ Kinase activity

66-68

Mst1

Caspase-dependent cleavage of an autoinhibitory domain

↑ Kinase activity

60

PKA

AKAP indicates a-kinase anchoring proteins: ASK-1, apoptosis signal-regulated kinase-1; CaMKII, Ca2+- and calmodulin-dependent protein kinase II; cTnC, cardiac troponin C; MHC, myosin heavy chain; Mst1, mammalian sterile 20-like kinase 1; PK, protein kinase: ROS, reactive oxygen species; and Trx-1, thioredoxin-1. Taken from Steinberg SF. Oxidative stress and sarcomeric proteins. Circ Res 112: 393-405, 2013.

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Table 13 Abbreviations ACC: American College of Cardiology

ICF: Impaired cerebral function

ACE: Angiotensin converting enzyme

LV: Left ventricle

ADH: Antidiuretic hormone

LVRR: Left ventricle reverse remodeling

ADH: Antidiuretic hormone

MCI: Mild cognitive impairment

ADM: Adrenomedullin

MCP-1α: Monocyte chemoattractant protein-1α

AHA: American Heart Association

MI: Myocardial infarction

ANP: Atrial natriuretic peptide

MMP: Matrix metalloproteinase

AT: Angiotensin

NAP-2: Neutrophil activating peptide-2

ATP: Adenosine triphosphate

NE: Norepinephrine

ATR: Angiotensin receptor

NET: Neutrophil extracellular traps

AVP: Arginine vasopressin

NO: Nitric oxide

BNP: Brain natriuretic peptide

NOS: Nitric oxide synthase

CAD: Coronary artery disease

NPR: Natriuretic peptide receptor

cAMP: Cyclic adenosine monophosphate

NSTEMI: Non-ST-elevation myocardial infarct

CHF: Chronic heart failure

NT-proBNP: N-terminal probrain-natriuretic peptide

CICR: Calcium-induced calcium release

NYHA: New York Heart Association

CIF: Cotransport inhibitory factor

PVA: Pressure-volume area

CIND: Cognitive impairment with no dementia

PV-Loop: Pressure-volume loop

CO: Cardiac output

RAAS: Renin angiotensin aldosterone system

COPD: Chronic obstructive pulmonary disease

RANTES: Regulated on activation normal T cell expressed and secreted

Ea: Arterial elastance ECM: Extracellular matrix

RED-HF: Reduction of events by darbepoetin alfa in heart failure

EDRF: Endothelium-derived relaxing factor

RWT: relative wall thickness

EF: Ejection fraction

RyR: Ryanodine receptor

ESC: European Society of Cardiology

SERCA: Sarco-endoplasmic reticulum calcium ATPase

EDPRV: End-diastolic pressure-volume relationship

STAMINA-HeFT: Study of Anemia in Heart Failure Trial

ESPRV: End-systolic pressure-volume relationship

STEMI: ST-elevation myocardial infarct

ET: Endothelin

SV: Stroke volume

GDF-15: Growth-differentiation factor-15

SW: Stroke work

GPCR: G-protein-coupled receptors

TACE: TNFα converting enzyme

GRK: GPCR receptor kinase

TIMP: Tissue inhibitor of metalloproteinase

GTP: Guanosine triphosphate

TNFR: TNFα receptor

HDAC: Histone deacetylase

XO: Xanthine oxidase

HF-PEF: Heart failure with preserved ejection fraction

UTR: Urotensin receptor

HF-REF: Heart failure with reduced ejection fraction

releasing cytochrome c, which represents an initiating signal for the apoptosis mediator caspase family. The fact, that mitochondrial high-energy phosphate formation is the major source for energy supply for cardiomyocytes, suggests that pathological changes in mitochondrial energy metabolism are strongly related to myocyte dysfunction, apoptosis, and development of heart failure (90, 92).

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Antioxidant systems The role of the endogenous antioxidant systems is to counterweigh the deleterious effects of ROS: the enzymatic and nonenzymatic antioxidants are the executor of the scavenge mechanisms of ROS. The intrinsic antioxidant effectors include enzymes such as catalase, glutathione peroxidase, superoxide dismutase, or nonenzymatic antioxidants like

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vitamin C, E (96), N-acetylcystein (137, or ubiquinone. These effectors convert ROS into harmless molecules, which are neutral in terms of apoptosis or oxidative damages. A further antioxidant system is represented by the thioredoxin system (70), including thioredoxin, thioredoxin-reductase, and NADPH, which acts as a protein-disulfide oxidoreductase. NO is a further well-known vasoactive and reactive molecule, which stimulates the formation of cGMP. Its target molecule, cGK-1 (protein kinase G1) modulates myocyte function and growth, and regulates remodeling.

Conclusions Initially, heart failure was viewed as a consequence of salt and water retention resulting from an impaired renal perfusion, in sense of a renocardial syndrome. Later on, the hemodynamic theory unfolded, which explained cardiac dysfunction as a combination of reduced CO and increased afterload. Both of these concepts describe cardinal features of heart failure, but neither of them explains its constant progression. Therefore, a novel progressive model of heart failure was established. The development of heart failure follows a primary cardiac event. It can occur acutely such as in myocardial infarction, or chronically such as in cardiomyopathies. Independently of the underlying cause, conserved macroand microstructural, cellular, and molecular processes are set into motion, following the same pathway and resulting in an impaired contractile function, increased peripheral resistance, and reduced peripheral organ perfusion. The compensatory mechanisms react on this altered cardiac functioning and maintain the cardiac homeostasis within certain range. Compensatory mechanisms include the neurohumoral system like the early activated adrenergic system or various bioactive molecules, inflammatory responses with different cytokines, chemokines, or molecular mechanisms. Architectural alterations in the evolution of heart failure, such as progressive hypertrophy, heart enlargement, and increased sphericity, define a well-traceable and monitorable group of factors. In the background of their development are however microstructural reorganization mechanisms: increased cardiomyocyte hypertrophy, apoptosis, and fibrotic changes in the extracellular matrix. Patients with reduced systolic or diastolic function appear often asymptomatic or minimally symptomatic for a long time; however, they may become rapidly symptomatic after an acute “decompensating” cardiac event. The typical symptoms of heart failure include dyspnea in many forms (dyspnea under physical exertion, orthopnea, paroxysmal nocturnal dyspnea, and cardiac asthma), fluid retention with different appearance, such as ankle edema, liver congestion, or malabsorption by wall edema in the gastrointestinal tract, or compensatory reactions like reflex tachycardia. Heart failure is considered a systemic disease with multiorgan effects. Besides clinically measurable organ dysfunctions, such as renal failure and anemia, neuropsychiatric symptoms

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may occur, presenting as a cardiogenic dementia or heart failure-induced depression. Great effort has been made to reverse the progressing remodeling processes to maintain a stable state. Beside novel, optimized pharmacotherapeutical regimes, interventional and surgical methods have also made a remarkable progression during the past decades. Reverse remodeling was successfully reached by many procedures, for instance, significant improvement could be detected after cardiac resynchronization therapy. The understanding of the pathophysiological mechanisms in the development of heart failure still remains in focus of cardiovascular medicine, not only because of its theoretically challenging, convoluted processes but because of its clinical importance for the design of novel therapeutical approaches.

Acknowledgements The authors wish to thank the following colleagues for their participation in the writing of this chapter: Dr. G. Ramos, Dr. J. Weirather, and Dr. B. Vogel. This work was supported by grants from the Bundesministerium fu¨r Bildung und Forschung (BMBF01 EO1004) (S. Frantz) and by the Deutsche Forschungsgemeinschaft, SFB688 TP A10 (S. Frantz).

References 1.

2.

3. 4. 5. 6.

7.

8. 9.

10.

Abbate A, Salloum FN, Vecile E, Das A, Hoke NN, Straino S, BiondiZoccai GG, Houser JE, Qureshi IZ, Ownby ED, Gustini E, Biasucci LM, Severino A, Capogrossi MC, Vetrovec GW, Crea F, Baldi A, Kukreja RC, Dobrina A. Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 117: 2670-2683, 2008. Adams KF Jr, Sueta CA, Gheorghiade M, O’Connor CM, Schwartz TA, Koch GG, Uretsky B, Swedberg K, McKenna W, Soler-Soler J, Califf RM. Gender differences in survival in advanced heart failure: Insights from the FIRST study. Circulation 99: 1816-1821, 1999. Ahuja P, Sdek P, MacLellan WR. Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol Rev 87: 521-544, 2007. Al-Hesayen AP, Parker JD. Impaired baroreceptor control of renal sympathetic activity in human chronic heart failure. Circulation 109: 2862-2865, 2004. Ambardekar AV, Buttrick PM. Reverse remodeling with left ventricular assist devices: A review of clinical, cellular, and molecular effects. Circ Heart Fail 4: 224-233, 2011. Amir O RO, David M, Lahat N, Wolff R, Lewis BS. Circulating Interleukin-10: Association with higher mortality in systolic heart failure patients with elevated tumor necrosis factor-alpha. IMAJ 12: 158162, 2010. Anand IS, Latini R, Florea VG, Kuskowski MA, Rector T, Masson S, Signorini S, Mocarelli P, Hester A, Glazer R, Cohn JN, Val-HeFT Investigators. C-reactive protein in heart failure: Prognostic value and the effect of valsartan. Circulation 112: 1428-1434, 2005. Anand I, McMurray JJ, Whitmore J, Warren M, Pham A, McCamish MA, Burton PB. Anemia and its relationship to clinical outcome in heart failure. Circulation 110: 149-154, 2004. Andreassen AK, Nordøy I, Simonsen S, Ueland T, Mu¨ller F, Frøland SS, Gullestad L, Aukrust P. Levels of circulating adhesion molecules in congestive heart failure and after heart transplantation. Am J Cardiol 84: 604-608, 1998. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole-Wilson PA, Coats AJ. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. 96: 526-534, 1997.

211

Pathophysiology of Heart Failure

11. 12. 13. 14.

15. 16. 17. 18. 19. 20. 21.

22.

23. 24.

25.

26. 27. 28. 29. 30. 31. 32. 33. 34. 35.

36. 37. 38. 39. 40.

212

Arakawa HUaK. Angiotensin II-forming systems in cardiovascular diseases. Heart Fail Rev 3: 119-124, 1998. Auer J. What does the liver tell us about the failing heart? Eur Heart J 34: 711-714, 2013. Aukrust P, Gullestad L, Ueland T, Dama˚ s JK, Yndestad A. Inflammatory and anti-inflammatory cytokines in chronic heart failure: Potential therapeutic implications. Ann Med 37: 74-85, 2005. Aukrust P, Ueland T., Muller F., Andreassen AK, Nordoy I., Aas H, Kjekshus J, Simonsen S, Froland SS, Gullestad L. Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circulation 97: 1136-1143, 1998. Belmonte SL, Blaxall BC. G protein coupled receptor kinases as therapeutic targets in cardiovascular disease. Circ Res 109: 309-319, 2011. Bers DM. Cardiac excitation–contraction coupling. Nature 415: 198205, 2002. Bers DM. Altered cardiac myocyte Ca regulation in heart failure. Physiology 21: 380-387, 2006. Birnbaumer M. Vasopressin receptors. TEM 11: 406-410, 2000. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 11: 507-15, 2014. Bortone AS HO, Chiddo A, Gaglione A, Locuratolo N, Caruso G, Rizzon P. Functional and structural abnormalities in patients with dilated cardiomyopathy. JACC 14: 613-623, 1989. Braun J, Bax JJ, Versteegh MI, Voigt PG, Holman ER, Klautz RJ, Boersma E, Dion RA. Preoperative left ventricular dimensions predict reverse remodeling following restrictive mitral annuloplasty in ischemic mitral regurgitation. Eur J Cardiothorac Surg 27: 847-853, 2005. Bristow MR, Ginsburg, R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. N Engl J Med 307: 205-211, 1982. Carabello BA. Concentric versus eccentric remodeling. J Card Fail 8: S258-263, 2002. Celermajer DS, Chow CK, Marijon E, Anstey NM, Woo KS. Cardiovascular disease in the developing world: Prevalences, patterns, and the potential of early disease detection. J Am Coll Cardiol 60: 1207-1216, 2012. Cesselli D, Jakoniuk I, Barlucchi L, Beltrami AP, Hintze TH, NadalGinard B, Kajstura J, Leri A, Anversa P. Oxidative stress-mediated cardiac cell death is a major determinant of ventricular dysfunction and failure in dog dilated cardiomyopathy. Circ Res 89: 279-286, 2001. Chai SY, Fernando R, Peck G, Ye SY, Mendelsohn FA, Jenkins TA, Albiston AL. The angiotensin IV/AT4 receptor. Cell Mol Life Sci 61: 2728-2737, 2004. Chemla D, Coirault C, He´bert JL, Lecarpentier Y. Mechanics of relaxation of the human heart. News Physiol Sci 15: 78-83, 2000. Angermann CE, Frey A, Ertl G. Cognition matters in cardiovascular disease and heart failure. Eur Heart J 33: 1721-3, 2012. Chung I, Choudhury A, Patel J, Lip GY. Soluble, platelet-bound, and total P-selectin as indices of platelet activation in congestive heart failure. Ann Med 41: 45-51, 2009. Davis JO, Urquhart J, Higgins JT, Jr. Renin, angiotensin and aldosterone in experimental secondary hyperaldosteronsimus. Canad Med Assoc J 90: 245-248, 1964. de Simone G. Concentric or eccentric hypertrophy: How clinically relevant is the difference? Hypertension 43: 714-715, 2004. Defer N, Azroyan A, Pecker F, Pavoine C. TNFR1 and TNFR2 signaling interplay in cardiac myocytes. J Biol Chem 282: 35564-35573, 2007. Dendorfer A, Thornagel A, Raasch W, Grisk O, Tempel K, Dominiak P. Angiotensin II induces catecholamine release by direct ganglionic excitation. Hypertension 40: 348-354, 2002. Deschamps AM, Spinale FG. Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation. Cardiovasc Res 69: 666-676, 2006. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, Lee RT. Targeted deletion of matrix metalloproteinase-9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infarction. J Clin Invest 106: 55-62, 2000. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245: C1-14, 1983. Feldman AM CA, Wagner D, Kadakomi T, Kubota T, Li YY, McTiernan C. The Role of Tumor Necrosis Factor in the Pathophysiology of Heart Failure. J Am Coll Cardiol 35: 537-544, 2000. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87: 241-247, 2000. Frank JS, Langer GA. The myocardial interstitium: its structure and its role in ionic exchange. J Cell Biol 60: 586-601, 1974. Gaasch WH, Battle WE, Oboler AA, Banas JS, Levine HJ. Left ventricular stress and compliance in man: With special reference to normalized ventricular function curves. Circulation 45: 746-762, 1972.

Comprehensive Physiology

41. 42.

43. 44. 45. 46.

47.

48. 49. 50. 51.

52.

53. 54. 55. 56. 57. 58. 59. 60.

61.

62. 63. 64. 65. 66. 67.

Gjesdal O, Bluemke DA, Lima JA. Cardiac remodeling at the population level–risk factors, screening, and outcomes. Nat Rev Cardiol 8: 673685, 2011. Glower DD, Spratt JA, Snow ND, Kabas JS, Davis JW, Olsen CO, Tyson GS, Sabiston DC, Rankin JS. Linearity of the Frank-Starling relationship in the intact heart: The concept of preload recruitable stroke work. Circulation 71: 994-1009, 1985. Gnansekaran G. Epidemiology of depression in heart failure. Heart Fail Clin 7: 1-10, 2011. Goldsmith SR. The role of vasopressin in congestive heart failure. Cleve Clin J Med 73: S19-S23, 2006. Gomez AM, Guatimosim S, Dilly KW, Vassort G, Lederer WJ. Heart failure after myocardial infarction: Altered excitation-contraction coupling. Circulation 104: 688-693, 2001. Goonasekera SA, Hammer K, Auger-Messier M, Bodi I, Chen X, Zhang H, Reiken S, Elrod JW, Correll RN, York AJ, Sargent MA, Hofmann F, Moosmang S, Marks AR, Houser SR, Bers DM, Molkentin JD. Decreased cardiac L-type Ca(2)(+) channel activity induces hypertrophy and heart failure in mice. J Clin Invest 122: 280-290, 2012. Griselli M, Herbert H, Hutchinson WL, Taylor KM, Sohail M, Krausz T, Pepys MB. C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med 190: 17331739, 1999. Halade GV, Jin YF, Lindsey ML. Matrix metalloproteinase (MMP)-9: A proximal biomarker for cardiac remodeling and a distal biomarker for inflammation. Pharmacol Ther 139: 32-40, 2013. Heinrich PC BI, Mu¨ller-Newen G, Schaper F, Graeve L. Interleukin6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334: 297-314, 1998. Iribarren C, Karter AJ, Go AS, Ferrara A, Liu JY, Sidney S, Selby JV. Glycemic control and heart failure among adult patients with diabetes. Circulation 103: 2668-2673, 2001. Ishikawa Y, Sorota S, Kiuchi K, Shannon RP, Komamura K, Katsushika S, Vatner DE, Vatner SF, Homcyl CJ. Downregulation of adenylylcyclase types V and VI mRNA levels in pacing-induced heart failure in dogs. J Clin Invest 93: 2224-2229, 1994. Jensen BC, O’Connell TD, Simpson PC. Alpha-1–adrenergic receptors in heart failure: The adaptive arm of the cardiac response to chronic catecholamine stimulation. J Cardivasc Phar 63: 291-301, 2014. Kameda K. Correlation of oxidative stress with activity of matrix metalloproteinase in patients with coronary artery disease: Possible role for left ventricular remodelling. Eur Heart J 24: 2180-2185, 2003. Kanellakis P, Ditiatkovski M, Kostolias G, Bobik A. A pro-fibrotic role for interleukin-4 in cardiac pressure overload. Cardiovasc Res 95: 77-85, 2012. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 241: 2035-2038, 1979. Kardys I, Knetsch AM, Bleumink GS, Deckers JW, Hofman A, Stricker BH, Witteman JC. C-reactive protein and risk of heart failure. The Rotterdam Study. Am Heart J 152: 514-520, 2006. Kaschina E, Unger T. Angiotensin AT1/AT2 receptors: Regulation, signalling and function. Blood Press 12: 70-88, 2003. Kehat I, Molkentin JD. Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation 122: 27272735, 2010. Kim HNJ, J. L., Jr. Natriuretic peptide testing in heart failure. Circulation 123: 2015-2019, 2011. Kim J, Eckhart AD, Eguchi S, Koch WJ. Beta-adrenergic receptormediated DNA synthesis in cardiac fibroblasts is dependent on transactivation of the epidermal growth factor receptor and subsequent activation of extracellular signal-regulated kinases. J Biol Chem 277: 3211632123, 2002. Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE. Left ventricular remodeling in heart failure: Current concepts in clinical significance and assessment. JACC Cardiovasc Imaging 4: 98-108, 2011. Kubo H, Jaleel N, Kumarapeli A, Berretta RM, Bratinov G, Shan X, Wang H, Houser SR, Margulies KB. Increased cardiac myocyte progenitors in failing human hearts. Circulation 118: 649-657, 2008. Lane RE, Cowie MR, Chow AW. Prediction and prevention of sudden cardiac death in heart failure. Heart 91: 674-680, 2005. Lazzarini V, Mentz RJ, Fiuzat M, Metra M, O’Connor CM. Heart failure in elderly patients: Distinctive features and unresolved issues. Eur J Heart Fail 15: 717-723, 2013. Lefkowitz RJ, Rockman HA, Koch WJ. Catecholamines, cardiacadrenergic receptors, and heart failure. Circulation 101: 1634-1637, 2000. Lieber C, Mohsenin V. Cheyne-Stokes respiration in congestive heart failure. Yale J Biol Med 65: 39-50, 1992. Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by transforming growth factor-beta(1). Mol Genet Metab 71: 418-435, 2000.

Volume 6, January 2016

Comprehensive Physiology

68. 69. 70. 71.

72. 73. 74.

75.

76.

77. 78. 79. 80. 81. 82.

83. 84. 85. 86. 87. 88. 89. 90.

91.

92.

Lombardo TA, Harrison TR. Cardiac asthma. Circulation 4: 920-929, 1951. Lorell BH, Carabello BA. Left ventricular hypertrophy: Pathogenesis, detection, and prognosis. Circulation 102: 470-479, 2000. Lu J, Holmgren A. The thioredoxin antioxidant system. Free Radic Biol Med 66: 75-87, 2014. Luchner A, Henqstenberg C, Lowel H, Riegger GA, Schunkert H, Holmer S. Effect of compensated renal dysfunction on approved heart failure markers: Direct comparison of brain natriuretic peptide (BNP) and N-terminal pro-BNP. Hypertension 46: 118-123, 2005. MacLennan DH, Kranias EG. Phospholamban: A crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol 4: 566-577, 2003. Madamanchi A. β-Adrenergic receptor signaling in cardiac function and heart failure. MJM 10: 99-107, 2007. Maekawa Y, Anzai T, Yoshikawa T, Asakura Y, Takahashi T, Ishikawa S, Mitamura H, Ogawa S. Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction: A possible role for left ventricular remodeling. J Am Coll Cardiol 39: 241-246, 2002. Maisel A, Mueller C, Adams KJr, Anker SD, Aspromonte N, Cleland JG, Cohen-Solal A, Dahlstrom U, DeMaria A, Di Somma S, Filippatos GS, Fonarow GC, Jourdain P, Komajda M, Liu PP, McDonagh T, McDonald K, Mebazaa A, Nieminen MS, Peacock WF, Tubaro M, Valle R, Vanderhyden M, Yancy CW, Zannad F, Braunwald E. State of the art: Using natriuretic peptide levels in clinical practice. Eur J Heart Fail 10: 824-839, 2008. Marantz PR, Tobin JN, Wassertheil-Smoller S, Steingart RM, Wexler JP, Budner N, Lense L, Wachspress J. The relationship between left ventricular systolic function and congestive heart failure diagnosed by clinical criteria. Circulation 77: 607-612, 1988. Maron BJ. Distinguishing hypertrophic cardiomyopathy from athlete’s heart: A clinical problem of increasing magnitude and significance. Heart 91: 1380-1382, 2005. Maron BJ, Pelliccia A. The heart of trained athletes: Cardiac remodeling and the risks of sports, including sudden death. Circulation 114: 16331644, 2006. Martin M, Requero JJ, Castro MG, Coto E, Hernandez E, Carro A, Calvo D, de la Tassa CM. Hypertrophic cardiomyopathy and athlete’s heart: A tale of two entities. Eur J Echocardiogr 10: 151-153, 2009. McDonagh TA. Asymptomatic left ventricular dysfunction in the community. Curr Cardiol Rep 2: 470-474, 2000. McEwan PE, Gray GA, Sherry L, Webb DJ, Kenyon CJ. Differential effects of angiotensin II on cardiac cell proliferation and intramyocardial perivascular fibrosis in vivo. Circulation 98: 2765-2773, 1998. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH, Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A, ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 33: 1787-1847, 2012. Mehta PA, Dubrey SW. High output heart failure. QJM 102: 235-241, 2009. Mehta J, Dinerman J, Mehta P, Saldeen TG, Lawson D, Donnelly WH, Wallin R. Neutrophil function in ischemic heart disease. Circulation 79: 549-556, 1989. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 93: 1137-1146, 2007. Movsesian MA, Karimi M, Green K, Jones LR. Ca(2+)-transporting ATPase, phospholamban, and calsequestrin levels in nonfailing and failing human myocardium. Circulation 90: 653-657, 1994. Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 417: 1-13, 2009. Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: Protagonists of infarct inflammation and repair after myocardial infarction. Circulation 121: 2437-2445, 2010. Naughton MT. Pathophysiology and treatment of Cheyne-Stokes respiration. Thorax 53: 514-518, 1998. Nojiri N, Shimizu T, Funakoshi M, Yamaguchi O, Zhou H, Kawakami S, Ohta Y, Sami M, Tachibana T, Ishikawa H, Kurosawa H, Kahn RC, Otsu K, Shirasawa T. Oxidative stress causes heart failure with impaired mitochondrial respiration. J Biol Chem 281: 33789-33801, 2006. O’Connell TD, Jensen BC, Baker AJ, Simpson PC. Cardiac alpha1adrenergic receptors: Novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. Pharmacol Rev 66: 308-333, 2014. Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485: 251-255, 2012.

Volume 6, January 2016

Pathophysiology of Heart Failure

93. 94. 95. 96. 97.

98.

99. 100. 101. 102. 103.

104. 105. 106. 107. 108. 109. 110.

111. 112. 113. 114.

115. 116. 117. 118. 119.

120.

121.

Ouzounian M, Lee DS, Liu PP. Diastolic heart failure: Mechanisms and controversies. Nat Clin Pract Cardiovasc Med 5: 375-386, 2008. Ozawa Y, Smith D, Craige E. Origin of the third heart sound. II. Studies in human subjects. Circulation 67: 399-404, 1983. Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: New drugs, old concerns? Curr Pharm Des 10: 2463-2475, 2004. Palace VP, Hill MF, Farahmand F, Singal PK. Mobilization of antioxidant vitamin pools and hemodynamic function after myocardial infarction. Circulation 99: 121-126, 1999. Park JH, Negishi K, Grimm RA, Popovic Z, Stanton T, Wilkoff BL, Marwick TH. Echocardiographic predictors of reverse remodeling after cardiac resynchronization therapy and subsequent events. Circ Cardiovasc Imaging 6: 864-872, 2013. Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 440: 12171221, 2006. Periasamy M, Huke S. SERCA pump level is a critical determinant of Ca(2+)homeostasis and cardiac contractility. J Mol Cell Cardiol 33: 1053-1063, 2001. Piepoli M. Diagnostic and prognostic indicators in chronic heart failure. Eur Heart J 20: 1367-1369, 1999. Pieske B. Reverse remodeling in heart failure – fact or fiction? Eur Heart J Suppl 6: D66-D78, 2004. Rathi SS, Dhalla NS. Mechanism of cardioprotective action of TNF-α in the isolated rat heart. Exp Clin Cardiol 6: 146-150, 2002. Reaux A, Iturrioz X, Vazeux G, Fournie-Zaluski MC, David C, Roques BP, Corvol P, Llorens-Cortes C. Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure. Biochem Soc Trans 28: 435-440, 2000. Richards AM. The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides. Heart 76: 36-44, 1996. Riegger GA, Liebau G, Kochsiek K. Antidiuretic hormone in congestive heart failure. Am J Med 72: 49-52, 1982. Sabbah HN, Sharov VG, Lesch M, Goldstein S. Progression of heart failure: A role for interstitial fibrosis. Mol Cell Biochem 147: 29-34, 1995. Schrier RW. Cardiorenal versus renocardiac syndrome: Is there a difference? Nat Clin Pract Nephrol 3: 637, 2007. Sharma S. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J 18: 1692-1700, 2004. Sharma R, Coats AJ, Anker SD. The role of inflammatory mediators in chronic heart failure: Cytokines, nitric oxide, and endothelin-1. Int J Cardiol 72: 175-186, 2000. Sinning D, Kasner M, Westermann D, Schulze K, Schultheiss HP, Tschope C. Increased left ventricular stiffness impairs exercise capacity in patients with heart failure symptoms despite normal left ventricular ejection fraction. Cardiol Res Pract 2011: 692862, 2011. Slavikova J, Kuncova J, and Topolcan O. Plasma catecholamines and ischemic heart disease. Clin Cardiol 30: 326-330, 2007. Smallie T, Ricchetti G, Horwood NJ, Feldmann M, Clark AR, Williams LM. IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages. J Exp Med 207: 2081-2088, 2010. Steinberg SF. Oxidative stress and sarcomeric proteins. Circ Res 112: 393-405, 2013. Suskin N MR, Burns RJ, Latini R, Pericak D, Probstfield J, Rouleau JL, Sigouin C, Solymoss CB, Tsuyuki R, White M, Yusuf S. Glucose and insulin abnormalities relate to functional capacity in patients with congestive heart failure. Eur Heart J 16: 1368-1375, 2000. Sutton MS, Keane MG. Reverse remodelling in heart failure with cardiac resynchronisation therapy. Heart 93: 167-171, 2007. Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertension 49: 241-248, 2007. Tang YD, Katz SD. Anemia in chronic heart failure: Prevalence, etiology, clinical correlates, and treatment options. Circulation 113: 24542461, 2006. Tarzami ST. Chemokines and inflammation in heart disease: Adaptive or maladaptive? Int J Clin Exp Med 4: 74-80, 2011. Thibodeau JT, Turer AT, Gualano SK, Ayers CR, Velez-Martinez M, Mishkin JD, Patel PC, Mammen PP, Markham DW, Levine BD, Drazner MH. Characterization of a novel symptom of advanced heart failure: Bendopnea. JACC Heart failure 2: 24-31, 2014. Tousoulis D, Homaei H, Ahmed N, Asimakopoulos G, Zouridakis E, Toutouzas P, Davies GJ. Increased plasma adhesion molecule levels in patients with heart failure who have ischemic heart disease and dilated cardiomyopathy. Am Heart J 141: 277-280, 2001. Udelson JE. Heart failure with preserved ejection fraction. Circulation 124: e540-543, 2011.

213

Pathophysiology of Heart Failure

122. Unger T CO, Csikos T, Culman J, Gallinat S, Gohlke P, Ho¨hle S, Meffert S, Stoll M, Stroth U, Zhu YZ. Angiotensin receptors. J Hypertens Suppl 14: S95-104, 1996. 123. Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse MJ. Altered expression of beta-adrenergic receptor kinase and beta 1- adrenergic receptors in the failing human heart. Circulation 87: 454-463, 1993. 124. van Empel VP, Bertrand AT, Hofstra L, Crijns HJ, Doevendans PA, De Windt LJ. Myocyte apoptosis in heart failure. Cardiovasc Res 67: 21-29, 2005. 125. van Empel VP, De Windt LJ. Myocyte hypertrophy and apoptosis: A balancing act. Cardiovasc Res 63: 487-499, 2004. 126. Ventura-Clapier R, Garnier A, Veksler V. Energy metabolism in heart failure. J Physiol 555: 1-13, 2004. 127. Ventura-Clapier R, Garnier A, Veksler V, Joubert F. Bioenergetics of the failing heart. Biochim Biophys Acta 1813: 1360-1372, 2011. 128. Voelkel NF, Quaife RA, Leinwand LA, Barst RJ, McGoon MD, Meldrum DR, Dupuis J, Long CS, Rubin LJ, Smart FW, Suzuki YJ, Gladwin M, Denholm EM, Gail DB, National Heart, Lung, and Blood Institute Working Group on Cellular Molecular Mechanisms of Right Heart, Failure. Right ventricular function and failure: Report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation 114: 18831891, 2006. 129. Waldum B, Stubnova V, Westheim AS, Omland T, Grundtvig M, Os I. Prognostic utility of B-type natriuretic peptides in patients with heart failure and renal dysfunction. Clin Kidney J 6: 55-62, 2013. 130. Weber KT. Cardiac interstitium in health and disease: The fibrillar collagen network. J Am Coll Cardiol 13: 1637-1652, 1989. 131. Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosis and renin-angiotensin-aldosterone system. Circulation 83: 1849-1865, 1991. 132. Weirather J, Hofmann UD, Beyersdof N, Ramos GC, Vogel B, Frey A, Ertl G, Kerkau T, Frantz S. Foxp3 +CD4+ T cells improve heal-

214

Comprehensive Physiology

133.

134. 135. 136. 137. 138. 139.

140. 141.

142.

ing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res 115: 55-67, 2014. Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschope C. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation 117: 2051-2060, 2008. Winslow RL, Rice J, Jafri S, Marban E, O’Rourke B. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, II: Model studies. Circ Res 84: 571-586, 1999. Wisneski JA, Bristow JD. Left vetricular stiffness. Ann Rev Med 29: 475-483, 1978. Wollert KC, Drexler H. The role of interleukin-6 in the failing heart. Heart Fail Rev 6: 95-103, 2001. Wu X-Y, Luo AY, Zhou YR, Ren JH. Nacetylcysteine reduces oxidative stress, nuclear factorkappaB activity and cardiomyocyte apoptosis in heart failure. Mol Med Rep 10: 615-624, 2014. Yi XP, Gerdes AM, Li F. Myocyte redistribution of GRK2 and GRK5 in hypertensive, heart-failure-prone rats. Hypertension 39: 1058-1063, 2002. Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, Taegtmeyer H. Impaired long chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes 51: 2587-2595, 2002. Liu Y, Leri A, Li B, Wang X, Cheng W, Kajstura J, Anversa P. Angiotensin II stimulation in vitro induces hypertrophy of normal and postinfarcted ventricular myocytes. Circ Res 82: 1145-1159, 1998. Zhang D, Fan GC, Zhou X, Zhao T, Pasha Z, Xu M, Zhu Y, Ashraf M, Wang Y. Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. J Mol Cell Cardiol 44: 281-292, 2008. Zouggari Y. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med 19: 12731280, 2013.

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