Pathophysiology of Heart Failure PDF

JWBT335-c140055
JWBT335-CompPhys-3G-v1
Printer: Yet to Come
November 25, 2015 10:11 8in10.75in
Pathophysiology of Heart Failure

Edit Tanai1,2 and 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 whichafter cardiac
injurystructural, 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 unspecic 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 ne 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.
Denition 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
Volume 6, January 2016
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 patients
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 stefan.frantz@uk-halle.de
Dept. of Internal Medicine I, University Hospital Wurzburg,
Germany
2 Comprehensive Heart Failure Center, University of Wurzburg,
Germany
3 Universitatsklinik und Poliklinik fur Innere Medizin III,
Universitatsklinikum Halle (Saale), Halle (Saale), Germany
Published online, January 2016 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c140055
Copyright American Physiological Society.
1
187
JWBT335-c140055
Table 1
Comprehensive Physiology
New York Heart Association (NYHA) Functional Classica-
tion
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 cmH2 O in the right atrium)

Jugular vein distension
Pleural effusion
Acute pulmonary edema
Decrease in vital capacity by

one-third from max.
Hepatojugular reux
Weight loss >4.5 kg/5 days in
response to treatment
Table 3
Classication 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
188
November 25, 2015 10:11 8in10.75in
In this stage, not only the primary disease should be properly treated, but a symptomatic therapy should be carried out
to maintain the patients 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 failureat 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
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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).
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
Diabetes mellitus
Diabetes mellitus
Arterial hypertension
Valvular heart disease
Arrhythmia
Hypertrophic cardiomyopathy
Inammatory 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
Hematological diseases:
Anemia, Polycythemia vera,
Beta-Thalassemia
Hyperthyreosis, thyrotoxicosis
Cardiomyopathies
Beriberi (vitamin B1 depletion)
Glomerulonephritis
Pericardial diseases
Skeletal diseases: Pagets

disease, McCune-Albright
syndrome, Multiple myeloma
Carcinoid syndrome
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. Otherstill
commoncauses 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.
r High blood pressure
Pregnancy (physiologic)
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 (right

ventricle MI)
Hypertension
COPD
Myocarditis
Pulmonary hypertension
Hypothyroidism
Pulmonary valve stenosis
Heart valve disease
Pulmonary embolism
Neuromuscular disease
r CAD, myocardial ischemia, and myocardial infarction

r Hyperglycemia, impaired glucose tolerance, and diabetes
189
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
r Hypercholesteremia
r Obstructive sleep apnea
r Drug abuse and excessive alcohol consumption
r Connective tissue disorders (systemic lupus erythematosus,
sarcoidosis, and amyloidosis)
r Congenital heart defects

r Family history
r Smoking
r Obesity
r Viral infections
r Arrhythmias
Classication
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
190
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).
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
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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
Vascular
Hormonal
Autonomic
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).
Vasopressin (ADH)
Volume overload
Circulating
catecholamines
Tachycardia
Signs, Symptoms, and Systemic Effects
Natriuretic peptides
Hyponatremia
Increased sympathetic
adrenergic activity
Tachycardia
Reduced vagal activity
Tachycardia
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.
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
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
191
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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 whichdue to
192
the central insensitivityarterial 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 cmH2 O. 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 cmH2 O) 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
ofusually moderateanemia (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
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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 congestionincluding the
bowels or the liveris 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
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 thepartially renal
eliminatedheart 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
193
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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.
Table 6
Shift along the Frank-Starling Curve and Its Causes

Right
Left
Isolated
Upward
Treatment with
positive inotrope
Isolated diastolic
dysfunction
Downward
Depressed
contractility
Decreased
contractility
increased
afterload
Increased
cardiac
performance
Isolated
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 =
(LVEDPLVEDR)/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 Laplaces 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,
194
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 hearts systolic reserve. The changes, shifts in
the Frank-Starling curve and their causes are represented in
Table 6.
Laplaces 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
r Elevated afterload (increased left ventricular pressure)

r Arterial hypertension
r Aortic valve stenosis
r Systolic heart failure with left ventricular dilation
(increased left ventricular radius)
r Valvular heart diseases

r Cardiomyopathies
r Increased left ventricular wall thickness
r Chronic hypertension
r Aortic valve stenosis
r Hypertrophic obstructive cardiomyopathy
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
Pressure-volume loop
LV pressure
(mmHg)
160
Normal
Decreased afterload
Increased afterload
Increased inotropy
Decreased inotropy
80
0
0
ESV 100
EDV
LV volume (mL)
200
Figure 1 PV loop showing the correlation of pressure and volume alterations in

physiological and pathological conditions.
r Decreased left ventricular wall thickness

r 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 ventricles 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
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/E +
P, where P defines pressure at time point t, P0 shows
amplitude constant, E is the Glantz relaxation constant,
and P 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
195
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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 athletes
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
Decreased SV and CO
Ventricular hypertrophy
Increased end-diastolic
pressure
Increased ventricular
stiffness
Impaired lling
(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
196
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 -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 TNF. 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 -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 andin extreme casesto 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
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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 brosis
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
TGF (67), PDGF, FGF, by different cytokines, such as IL-1,
IL-4 (54), tumor necrosis factor (TNF) 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
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/athletes heart syndrome/AHS is a physiological adaptive condition presenting in young sportsmencommonly
in endurance athleteswith 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.
197
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
Normal
Physiological state
Physiological myocardial mass, diameter,

wall thickness
Concentric
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 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 hearts mechanical and functional
198
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).
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
Ventricular compliance is the ability of the heart chamber to

distend and elevate the transmural pressure to increase its
volume.
Table 8
Biomarkers in Heart Failure
Neurohormones
Norepinephrine (NE)
Renin
Activation of the Neurohumoral System
Angiotensin II (AT-II)
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.
Arginine vasopressin/ADH
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 1-adrenergic activation, the myocardial
Aldosterone
ET-1
Myocyte strain
specic 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
Heart-type fatty-acid protein
Proinammatory
mediators
CRP
Cytokines: TNF, IL-6
Chemokines: MCP-2, IL-8, NAP-2, GRO-
Fas (APO-1)
Oxidative stress
components
Myeloperoxidase
Xanthine oxidase and uric acid
Allantoin
Oxidized LDL
1-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 1- or uncoupling of 2-adrenergic receptors. The activation of the 1-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
199
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
Table 9
Biological Effects of Activated Cardiac Adrenergic Receptors
Adrenergic
receptor
Benecial effect
Harmful effect
1c
Positive inotropy
Myocyte damage
Proarrhythmic
Vasoconstriction
Positive inotropy
Myocyte damage,
apoptosis
Positive chronotropy
Fetal gene induction
Vasodilation
(epicardial)
Proarrhythmic
Positive lusitropy
2
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 -adrenergic receptor subtypes; -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) Gs 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.
2AR
1AR
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
Figure 3
200
Inotropy
Hypertrophy
Lusitropy
Inotropy
Apoptosis
Beta-adrenergic signaling pathways and their effects in the heart.
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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
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 majorG-protein receptor associatedreceptors
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.
201
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
Angiotensinogen
Renin
Angiotensin I
ACE
Angiotensin 1-7
Angiotensin II
ACE 2
Further
metabolization
AT1
AT2
AT3+AT4
Vascoconstriction
Hypertrophy
Proliferation
Na+ retention
Oxidation
Inflammation
Thrombosis
NO
Antiproliferation
Vasodilation
Anti-inflammation
Antioxidative
Laminin
PAI-1
NO
ET
TIMP-1
Effects
APA
Angiotensin III
APN
Angiotensin IV
Heart
Interst
Fibrosy
Heart
Failure
Figure 4
Aldosterone
Other effects
(endothelial
dysfunction,
Salt and
fluid retention platelet
aggregation,
K+ secretion
etc.)
Kidney
Congestion,
electrolyte
imbalance
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
202
Adrenal
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
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
Table 10
Distribution
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 (broblasts,
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
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 TNF, interleukin 1 (IL-1), and 6 (IL-6). These are
secreted from the myocardium and mononuclear cells.
TNF
TNF 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 TNF, in contrast, after an acute injury the
concentration of TNF raises significantly. Myocyte stretch,
ischemia, pressure, or volume overload are thought to potentiate TNF production as well (37). TNF was found to increase
203
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
the expression of antioxidant enzyme manganese superoxide

dismutase and mitochondrial protein A20, in sense of a protective role in the heart. TNF 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. TNF 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
TNF cell membrane receptors defined so far, TNFR-1 and
TNFR-2. TNFR-1 is widely expressed and transmits deleterious effects of TNF. TNFR-2 is thought to exert the adaptive,
protective effect in the heart (32).
Anti-inammatory 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 TNF (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 TNF-level had
significant higher mortality (6).
Chemokines
IL-1 is made up of two distinct ligands, IL-1 and IL-1,

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 TNF. 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-1 and RANTES (118).
There are also neutrophil-specific chemokines, the CXC
chemokines, including IL-8, neutrophil activating peptide-2
and GRO, 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 TNF 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 proinammatory 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
204
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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).
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
205
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
Na+
K+
Na+/Ca2+
exchanger
3
Na+
Ca2+
Ryanodine
Ca2+
Sarcoplasmic
reticulum
Ca2+
ATPase
Ca2+
K+
Na+
Ca2+
Ca2+ -uptake
pump
Na+/K+
pump
L-type Ca2+
channel
Figure 5
Sarcomere
Ca2+ Troponin
complex
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 cycleafter 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.
206
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).
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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 TNF. 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
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
207
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
ROS
MAPK
JNK, p38, Akt
RyR
NF-
AP-1
DNA
damage
PARP-1
activation
Nucleus
Sarcoplasmic
reticulum
Inflammation
Apoptosis
Necrosis
Figure 6
Contractile
dysfunction
Mitochondrium
Fibrosis
Apoptosis
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-B) 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 (H2 O2 ). 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 (H2 O2 ) production. H2 O2 is able to generate the
formation of the highly reactive hydroxyl radicals via Fenton
208
MMPs
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, adrenergic agonists, endothelin-1, or tumor necrosis factor )
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
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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 -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
Table 12
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 forceprovides 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
Oxidative Modications of Protein Kinases

Rl subunit oxidation
R1 binding to AKAPs (-MHC)

PKAI kinase activity
Catalytic domain Cys199 -S-glutathionylation
Kinase activity
34-36
PKG 1
Oxidation of Cys42 in the homodimerization domain
Afnity 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
PKC catalytic activity

PKC-dependent phosphorylation of
14-3-3
8.85-87
Oxidation of a conserved activation loop Cys
Kinase activity
36, 59
Altered substrate specicity, acquisition of

cTnl-T144 kinase activity
40
PKA
Src-dependent phosphorylation of PKC at
Tyr311
32
PKD
c-Abl- and Src-dependent phosphorylations of PKD at

Tyr463 and Tyr95 that relieve autoinhibition, promote
PKC-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
PKC). 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
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.
209
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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-1: Monocyte chemoattractant protein-1
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: TNF converting enzyme
GRK: GPCR receptor kinase
TIMP: Tissue inhibitor of metalloproteinase
GTP: Guanosine triphosphate
TNFR: TNF 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).
210
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
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
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
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 fur Bildung und Forschung (BMBF01 EO1004) (S. Frantz) and by
the Deutsche Forschungsgemeinschaft, SFB688 TP A10 (S.
Frantz).
References
1.
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.
2. Adams KF Jr, Sueta CA, Gheorghiade M, OConnor 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.
3. Ahuja P, Sdek P, MacLellan WR. Cardiac myocyte cell cycle control
in development, disease, and regeneration. Physiol Rev 87: 521-544,
2007.
4. Al-Hesayen AP, Parker JD. Impaired baroreceptor control of renal
sympathetic activity in human chronic heart failure. Circulation 109:
2862-2865, 2004.
5. 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.
6. 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.
7. 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.
8. 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.
9. Andreassen AK, Nordy I, Simonsen S, Ueland T, Muller F, Frland
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.
10. 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
JWBT335-c140055
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, Damas 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 excitationcontraction 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 -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, Hebert 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.
November 25, 2015 10:11 8in10.75in
41. Gjesdal O, Bluemke DA, Lima JA. Cardiac remodeling at the population
levelrisk factors, screening, and outcomes. Nat Rev Cardiol 8: 673685, 2011.
42. 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.
43. Gnansekaran G. Epidemiology of depression in heart failure. Heart Fail
Clin 7: 1-10, 2011.
44. Goldsmith SR. The role of vasopressin in congestive heart failure. Cleve
Clin J Med 73: S19-S23, 2006.
45. Gomez AM, Guatimosim S, Dilly KW, Vassort G, Lederer WJ. Heart
failure after myocardial infarction: Altered excitation-contraction coupling. Circulation 104: 688-693, 2001.
46. 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.
47. 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.
48. 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.
49. Heinrich PC BI, Muller-Newen G, Schaper F, Graeve L. Interleukin6-type cytokine signalling through the gp130/Jak/STAT pathway.
Biochem J 334: 297-314, 1998.
50. 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.
51. 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.
52. Jensen BC, OConnell TD, Simpson PC. Alpha-1adrenergic receptors in heart failure: The adaptive arm of the cardiac response to
chronic catecholamine stimulation. J Cardivasc Phar 63: 291-301,
2014.
53. 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.
54. 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.
55. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The
Framingham study. JAMA 241: 2035-2038, 1979.
56. 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.
57. Kaschina E, Unger T. Angiotensin AT1/AT2 receptors: Regulation,
signalling and function. Blood Press 12: 70-88, 2003.
58. Kehat I, Molkentin JD. Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation 122: 27272735, 2010.
59. Kim HNJ, J. L., Jr. Natriuretic peptide testing in heart failure. Circulation 123: 2015-2019, 2011.
60. 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.
61. 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.
62. 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.
63. Lane RE, Cowie MR, Chow AW. Prediction and prevention of sudden
cardiac death in heart failure. Heart 91: 674-680, 2005.
64. Lazzarini V, Mentz RJ, Fiuzat M, Metra M, OConnor CM. Heart
failure in elderly patients: Distinctive features and unresolved issues.
Eur J Heart Fail 15: 717-723, 2013.
65. Lefkowitz RJ, Rockman HA, Koch WJ. Catecholamines, cardiacadrenergic receptors, and heart failure. Circulation 101: 1634-1637,
2000.
66. Lieber C, Mohsenin V. Cheyne-Stokes respiration in congestive heart
failure. Yale J Biol Med 65: 39-50, 1992.
67. Lijnen PJ, Petrov VV, Fagard RH. Induction of cardiac fibrosis by
transforming growth factor-beta(1). Mol Genet Metab 71: 418-435,
2000.
JWBT335-c140055
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. -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 athletes
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 athletes
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.
OConnell 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.
November 25, 2015 10:11 8in10.75in
93. Ouzounian M, Lee DS, Liu PP. Diastolic heart failure: Mechanisms and controversies. Nat Clin Pract Cardiovasc Med 5: 375-386,
2008.
94. Ozawa Y, Smith D, Craige E. Origin of the third heart sound. II. Studies
in human subjects. Circulation 67: 399-404, 1983.
95. Pacher P, Kecskemeti V. Cardiovascular side effects of new antidepressants and antipsychotics: New drugs, old concerns? Curr Pharm Des
10: 2463-2475, 2004.
96. Palace VP, Hill MF, Farahmand F, Singal PK. Mobilization of antioxidant vitamin pools and hemodynamic function after myocardial infarction. Circulation 99: 121-126, 1999.
97. 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.
98. 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.
99. 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.
100. Piepoli M. Diagnostic and prognostic indicators in chronic heart failure.
Eur Heart J 20: 1367-1369, 1999.
101. Pieske B. Reverse remodeling in heart failure fact or fiction? Eur
Heart J Suppl 6: D66-D78, 2004.
102. Rathi SS, Dhalla NS. Mechanism of cardioprotective action of TNF-
in the isolated rat heart. Exp Clin Cardiol 6: 146-150, 2002.
103. 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.
104. Richards AM. The renin-angiotensin-aldosterone system and the cardiac natriuretic peptides. Heart 76: 36-44, 1996.
105. Riegger GA, Liebau G, Kochsiek K. Antidiuretic hormone in congestive
heart failure. Am J Med 72: 49-52, 1982.
106. Sabbah HN, Sharov VG, Lesch M, Goldstein S. Progression of heart
failure: A role for interstitial fibrosis. Mol Cell Biochem 147: 29-34,
1995.
107. Schrier RW. Cardiorenal versus renocardiac syndrome: Is there a difference? Nat Clin Pract Nephrol 3: 637, 2007.
108. Sharma S. Intramyocardial lipid accumulation in the failing human
heart resembles the lipotoxic rat heart. FASEB J 18: 1692-1700, 2004.
109. 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.
110. 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.
111. Slavikova J, Kuncova J, and Topolcan O. Plasma catecholamines and
ischemic heart disease. Clin Cardiol 30: 326-330, 2007.
112. 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.
113. Steinberg SF. Oxidative stress and sarcomeric proteins. Circ Res 112:
393-405, 2013.
114. 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.
115. Sutton MS, Keane MG. Reverse remodelling in heart failure with cardiac resynchronisation therapy. Heart 93: 167-171, 2007.
116. Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy
and remodeling. Hypertension 49: 241-248, 2007.
117. Tang YD, Katz SD. Anemia in chronic heart failure: Prevalence, etiology, clinical correlates, and treatment options. Circulation 113: 24542461, 2006.
118. Tarzami ST. Chemokines and inflammation in heart disease: Adaptive
or maladaptive? Int J Clin Exp Med 4: 74-80, 2011.
119. 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.
120. 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.
121. Udelson JE. Heart failure with preserved ejection fraction. Circulation
124: e540-543, 2011.
213
JWBT335-c140055
November 25, 2015 10:11 8in10.75in
122. Unger T CO, Csikos T, Culman J, Gallinat S, Gohlke P, Hohle 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
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, ORourke 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.

Pathophysiology of Heart Failure PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Pathophysiology of Heart Failure PDF

Uploaded by

Copyright:

Available Formats

JWBT335-c140055

Printer: Yet to Come

November 25, 2015 10:11 8in10.75in