Heart Failure Pathophysiology PDF

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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 which—after cardiac
injury—structural, neurohumoral, cellular, and molecular mechanisms are activated and act as
a network to maintain physiological functioning. These coordinated, complex processes lead to
excessive volume overload, increased sympathetic activity, circulation redistribution, and result in
different, parallel developing clinical signs and symptoms. These signs and symptoms sum up to
an unspecific clinical picture; thus invasive and noninvasive diagnostic tools are used to get an
accurate diagnosis and to specify the underlying cause. The most important, outcome determin-
ing factor in heart failure is its constant progression. Constant optimizing of pharmatherapeutical
regimes, novel targets, and fine regulation of these processes try to keep these compensatory
mechanisms in a physiological range. Beside pharmacological therapy, interventional and surgi-
cal 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 treat-
ment, efforts should be made for better prevention in heart failure by treatment of risk factors, or
identifying and following risk groups. This summary of the pathophysiology of heart failure tries to
give a compact overview of basic mechanisms and of the novel unfolding, progressive theory of
heart failure to contribute to a more comprehensive knowledge of the disease. © 2016 American
Physiological Society. Compr Physiol 6:187-214, 2016.
Definition and Epidemiology the American Heart Association (AHA) to complement the
NYHA functional classification. This classification is also
Heart failure is defined as the inability of the heart to sup- based on the clinical signs and symptoms of the patient, thus
ply the peripheral tissues with the required amount of blood comprises the concomitant diseases and risk factors as well,
and oxygen to meet their metabolic demands. Pathophysio- to estimate the progression stage and outcome of the disease
logically, the cardiac output (for a list of abbreviations see (Table 3). Patients in stage A have no structural heart disease
table 13) is in its absolute or relative amount low and/or but an increased risk for developing heart failure over time.
has a pathological distribution. It leads to a clinical syn- Risk factors include hypertension, diabetes mellitus, and/or a
drome characterized by symptoms like dyspnea or fatigue, family history for cardiomyopathies. In this stage, risk factors
and signs such as elevated jugular venous pressure, tachycar- should be identified and treated to prevent the development of
dia, or peripheral edema. Heart failure is mostly caused by heart failure. Stage B presents with a structural heart disease
an underlying myocardial disease; however valve diseases, like myocardial infarction or valve disease in the patient’s
endocardial, or pericardial abnormalities and disorders in the history, although yet without clinical manifestations. In this
heart rate/rhythm may also result in cardiac malfunction. stage, the therapeutic strategy involves specific therapy of
The clinical severity of heart failure is graded according the underlying cause and optimizing of risk factors. In stage
to the New York Heart Association (NYHA) functional classi- C, clinically manifested heart failure occurs with the typical
fication based on the clinical symptoms and physical activity symptomatology of dyspnea, fatigue, and peripheral edema.
of the patient (Table 1).
The diagnosis of heart failure is generally made based
on the Framingham criteria, which involve manifested
* Correspondence to stefan.frantz@uk-halle.de
symptoms and clinical signs of the patient (76) (Table 2).
1 Dept. of Internal Medicine I, University Hospital Würzburg,
The diagnosis requires at least 2 major criteria, or 1 major
Germany
criterion with at least two minor criteria. Two or more minor 2 Comprehensive Heart Failure Center, University of Würzburg,
criteria are only accepted as diagnosis if they cannot be due Germany
to different organ failure like chronic lung disease [chronic 3 Universitätsklinik und Poliklinik für Innere Medizin III,
obstructive pulmonary disease (COPD)], liver cirrhosis or Universitätsklinikum Halle (Saale), Halle (Saale), Germany
nephrotic syndrome. Published online, January 2016 (comprehensivephysiology.com)
Another classification of chronic heart failure was estab- DOI: 10.1002/cphy.c140055
lished by the American College of Cardiology (ACC) and Copyright © American Physiological Society.
Volume 6, January 2016 187

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Pathophysiology of Heart Failure Comprehensive Physiology
Table 1 New York Heart Association (NYHA) Functional Classifica- In this stage, not only the primary disease should be prop-
tion erly treated, but a symptomatic therapy should be carried out
to maintain the patient’s “physical capacity” and to reduce
Class Severity of symptoms and physical activity symptoms of cardiac congestion. Beside adequate medical
treatment, a cardiac resynchronization therapy should also be
I. No limitation of physical activity. Ordinary physical activity discussed. Stage D means an end-stage heart failure, when the
does not cause undue breathlessness, fatigue, or maximal supportive and causative therapy is unable to provide
palpitations.
a stable state, and cardiac decompensation is not controllable,
II. Slight limitation of physical activity. Comfortable at rest, but reducible, or reversible for a long time. Cardiac transplan-
ordinary physical activity results in undue breathlessness,
fatigue, or palpitations. tation or mechanical circulatory support must be urgently
considered and carried out.
III. Marked limitation of physical activity. Comfortable at rest,
but less than ordinary physical activity results in undue In conclusion, the definition of heart failure according to
breathlessness, fatigue, or palpitations. the European Society of Cardiology (ESC) Task force (2012)
IV. Unable to carry on any physical activity without discomfort. includes: (i) Symptoms of heart failure—at rest or during
Symptoms at rest can be present. If any physical activity is exercise and (2) objective evidence (preferably by echocar-
undertaken, discomfort is increased. diography) 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
Table 2 Framingham Criteria for Congestive Cardiac Failure toward heart failure (82).
Heart failure is a highly frequent, “epidemic” disease in
Major criteria Minor criteria the modern world putting constantly pressure on clinical and
public health systems with its significant mortality, morbidity,
Paroxysmal nocturnal dyspnea Bilateral ankle edema and need for hospitalization. The lifetime risk of developing
Basal crepitations Dyspnea on ordinary exertion heart failure is approximately one in five for a 40-year-old
in Europe and North-America (85). The main risk factors of
(> 10 cm above the lung base)
heart failure include coronary artery disease (CAD), hyperten-
Third heart sound (S3 gallop) Tachycardia (>120 bpm) sion, diabetes mellitus (55), family history of cardiac diseases,
Cardiomegaly Nocturnal cough obesity, chronic pulmonary diseases, or use of cardiotoxins.
Increased central venous pressure Hepato(Spleno)megaly Among patients with diagnosed heart failure more than
50% present with low ejection fraction (EF) (i.e., HF-
(>12 cmH2 O in the right atrium)
REF=heart failure with reduced ejection fraction), and a little
Jugular vein distension Pleural effusion
less than 50% have preserved systolic function, mostly by
Acute pulmonary edema Decrease in vital capacity by reduced diastolic performance (HF-PEF = heart failure with
one-third from max.
preserved ejection fraction). There are some remarkable epi-
Hepatojugular reflux demiological and etiological differences between HF-REF
Weight loss >4.5 kg/5 days in and HF-PEF, namely, patients with HF-PEF are mostly older,
response to treatment more often female or obese, and have hypertension or atrial
fibrillation as an underlying cause of their cardiac dysfunc-
tion. It leads more often to cardiac decompensations and hos-
Table 3 Classification of Chronic Heart Failure According to the pital admissions, therapy resistance and incompliance occur
American College of Cardiology also more frequently (121). In contrast, the clinical population
with HF-REF is mainly characterized by an exactly defined
Stage Description cardiac disease as a cause: CAD, uncontrolled hypertension,
or heart valve failure.
A: High risk for developing Hypertension, diabetes mellitus, There are some differences in the incidence and preva-
heart failure family history of lence of heart failure considering special populations of age,
cardiomyopathy
sex, and ethnicity. Studies on heart failure indicate that the
B: Asymptomatic heart failure Previous myocardial infarction, prevalence and incidence of heart failure and its concomitant
left ventricle dysfunction,
valvular heart disease diseases are significantly higher in the older population (64).
Traditionally, 65 years of age has been considered as cut-off
C: Symptomatic heart failure Structural heart disease,
dyspnoea and fatigue, age for the definition of elderly, here occurs in approximately
impaired exercise tolerance 10% an impaired cardiac function. It is usually accompanied
D: Refractory end-stage heart Marked symptoms at rest by severe complications, frequent hospitalizations, and dif-
failure despite maximal medical ferent concomitant diseases. Heart failure has similar preva-
therapy lence rate in both sexes, but there are some small differences
in the development and specific features of the disease. Men
188 Volume 6, January 2016

Comprehensive Physiology Pathophysiology of Heart Failure
have higher incidence and prevalence but also worse outcome. Table 4 Etiology of Heart Failure
Women are significantly older (after menopause) at the time
point of the diagnosis, but survive longer after all (2). They Causes of systolic and diastolic heart diseases
have higher prevalence and incidence of diastolic dysfunc- Causes of systolic heart Causes of diastolic
tion, and/or hypertensive heart disease. Concerning the cause diseases diseases
of heart failure, a specific geographical distribution can be
drawn. In industrialized western countries, the most common Coronary artery disease Coronary artery disease
cause of heart failure is an ischemic heart disease, mainly Diabetes mellitus Diabetes mellitus
caused by a CAD. It is followed by arterial hypertension and
Arterial hypertension Arterial hypertension
valvular heart diseases. Rare diseases like Chagas’ disease or
cardiomyopathies are more likely in developing countries. It Valvular heart disease Valvular heart disease
should also be considered, that in developing countries the Arrhythmia Hypertrophic cardiomyopathy
average patient age is significant lower and therapeutic effi- Inflammatory diseases Restrictive cardiomyopathy
ciency and outcome of the disease are far poorer, compared
Peripartum cardiomyopathy Constrictive pericarditis
to the western world. However, these clear differences seem
to merge as a consequence of urbanization with its special Congenital heart disease
features like the negative changes of the eating habits and a Medications, drugs
more sedentary lifestyle, which lead to a significant increase (e.g., cocaine and
doxorubicin)
of diabetes, hypertension, or coronary heart disease (24).
Heart failure is a progressive disease, associated with an Idiopathic cardiomyopathy
annual mortality of approximately 10%. The main causes of
death in patients with heart failure is sudden cardiac death Causes of low-output and high-output heart failure
(>50%) (63) or multiple organ failure due to the chronic Causes of low-output heart Causes of high-output heart
systemic hypoperfusion. Despite rapidly developing therapy failure failure
strategies, heart failure has still a poor outcome with nearly
25% to 50% mortality rate in 5 years after diagnosis. It is Coronary artery disease Hematological diseases:
often caused by concomitant diseases especially by renal Anemia, Polycythemia vera,
Beta-Thalassemia
dysfunction, hypercholesterolemia, or anemia. Classic prog-
nostic factors for poor outcome are valvular regurgitation, Arterial hypertension Hyperthyreosis, thyrotoxicosis
ventricular arrhythmias, higher NYHA functional classes, Cardiomyopathies Beriberi (vitamin B1 depletion)
lower left ventricular EF, high level of N-terminal pro-B-type Valvular heart disease Glomerulonephritis
natriuretic peptide (NT-proBNP), or low serum sodium level;
Pericardial diseases Skeletal diseases: Paget’s
novel markers include autonomic dysfunction, oscillatory disease, McCune-Albright
breathing pattern, and insulin resistance (100). syndrome, Multiple myeloma
Carcinoid syndrome
Etiology and Risk Factors Pregnancy (physiologic)

Extreme obesity
The most common cause of heart failure is ischemic heart
disease due to impaired myocardial perfusion, mostly caused
Causes of left- and right-sided heart failure
by an acute or chronic myocardial ischemia. Other—still
Causes of left-sided heart Causes of right-sided heart
common—causes are cardiomyopathies (idiopathic or toxin- failure failure
induced, e.g., doxorubicin and alcohol), or valvular heart dis-
eases. There is no accepted standard for the etiological classi- Coronary artery disease Coronary artery disease (right
fication of heart failure; it can be divided into many subcate- ventricle MI)
gories according to the affected functional phase, circulation Hypertension COPD
system, volume status, etc. (Table 4).
Myocarditis Pulmonary hypertension
Risk factors include several medical states, which by
themselfes are enough to cause cardiac dysfunction; mostly a Hypothyroidism Pulmonary valve stenosis
combination of them occurs in patients with heart failure. Heart valve disease Pulmonary embolism
Neuromuscular disease
r High blood pressure
r CAD, myocardial ischemia, and myocardial infarction
r Hyperglycemia, impaired glucose tolerance, and diabetes

r Hypercholesteremia EF is normal (called heart failure with preserved ejection

fraction = HF-PEF), thus diagnosis and follow-up seem more
r Obstructive sleep apnea difficult, than in systolic heart failure. It is usually related to
chronic hypertension or ischemic heart disease but can be due
r Drug abuse and excessive alcohol consumption to restrictive, infiltrative, or hypertrophic cardiomyopathies
as well (19, 93).
r Connective tissue disorders (systemic lupus erythematosus,
sarcoidosis, and amyloidosis)
Pressure-overload versus volume-overload heart
r Congenital heart defects failure
Left ventricular dysfunction by pressure overload may
r Family history develop due to adverse left ventricle chamber remodeling,
decreased myocardial contractile function, or a combination
r Smoking of these. It mostly occurs in aortic valve stenosis and/or arte-
rial hypertension. Volume overload refers to the state when
r Obesity the heart chambers are overfilled with blood, which they try
to transmit into the systemic circulation. Various pathologies
r Viral infections can lead to volume overload, such as arteriovenous malforma-
tions and fistula, congenital heart diseases (persistent ductus
r Arrhythmias arteriosus and ventricular septal defect), or valvular heart dis-
eases (e.g., aortic regurgitation and mitral regurgitation). The
pulmonary circulation is also affected in valvular heart dis-
eases (tricuspid regurgitation and pulmonary regurgitation) or
Classification in congenital atrial septal defect.
Heart failure can be classified according to several pathophy-
siological or functional perspectives, such as the affected
circulatory system (right-left), cardiac function (systolic- Low-output versus high-output heart failure
diastolic), or the underlying pathophysiological factor Low-output means that the cardiac output (CO) fails to fulfill
(pressure-induced/volume-induced). 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, exces-
Systolic versus diastolic heart failure
sive preload, or excessive afterload:
For understanding the basic mechanisms and principles of the
pathophysiology of heart failure, a clear definition and under- 1. Pump failure (reduced inotropy)
standing of the primary mechanisms of systolic (HF-REF)
and diastolic (HF-PEF) heart failure are essential. Systolic a. Systolic heart failure
and diastolic heart failure are distinct syndromes with well- b. Relevant bradycardia
known pathophysiology, symptomatology, and epidemiology.
Not only differ development of impaired heart function, but c. Negative inotropic medications
also macro- and micromorphology of the heart, including the
cardiomyocytes or the extracellular matrix structure. Systolic 2. Excessive preload (volume overload)
heart failure is characterized by an impaired left ventricular a. Mitral regurgitation
contractility, resulting in a reduced EF. Therefore, this syn-
drome is also called heart failure with reduced left ventricular b. Aortic regurgitation
ejection fraction (HF-REF). The most common underlying
causes of systolic heart failure are ischemic heart disease, car- 3. Excessive afterload (pressure overload)
diomyopathies, and heart valve diseases. The main structural a. Aortic stenosis
change is an eccentric remodeling that is followed by pro-
gressive chamber dilation, and therefore a volume-overload, b. Hypertension
leading predominantly to forward heart failure. In contrast to
systolic, diastolic heart failure is accompanied by impaired High-output heart failure occurs when the CO is normal
ventricle relaxation and filling, increased ventricle stiffness, or elevated, to meet the increased requirements of the body,
and therefore, an elevated filling pressure as a response of but still fails to meet demands (83). Volume overload results
pressure overload. Diastolic heart failure is characterized by from chronic neurohumoral activation and progresses to
a concentric remodeling or ventricular hypertrophy resulting ventricular dilation and structural remodeling over time.
in pressure overload, and mainly backward heart failure. The Clinically, high-output heart failure presents with tachycardia

Table 5 Compensatory Mechanisms and Their Exhaustion in Heart circulation. In chronic cases, it shifts to the left atrium and
Failure reduces the systemic blood supply as well. To maintain a
sufficient preload, the systolic and diastolic pressure rises
Localization Compensated Decompensated in the right atrium, which leads to congestion in the gas-
trointestinal tract followed by anorexia, hepato-splenomegaly
Cardiac Frank-Starling mechanism Reduced EF with/without ascites, and anasarca by increased hydrostatic
Ventricular hypertrophy Ventricular dilation pressure in the capillaries. Right ventricular heart failure often
presents concomitant to a left ventricular dysfunction but
Tachycardia Arrhythmias
can also exist as an isolated cardiac failure, as a result of
Vascular Increased vascular tone Vasoconstriction a right ventricular myocardial infarction, chronic obstructive
Perfusion redistribution Peripheral hypoperfusion pulmonary disease, or pulmonary hypertension, or by rare dis-
Hormonal RAAS Hypertension, eases like severe tricuspidal regurge or arrhythmogenic right
vasoconstriction ventricle disease (128).
Vasopressin (ADH) Volume overload
Circulating Tachycardia
catecholamines Signs, Symptoms, and Systemic Effects
Natriuretic peptides Hyponatremia
The wide spectrum of clinical manifestations in heart failure
Autonomic Increased sympathetic Tachycardia can be divided into two main groups, as right and left
adrenergic activity
ventricle dysfunction, according to the affected circulatory
Reduced vagal activity Tachycardia 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,
jugular venous distension, and warm, sweaty skin. The compensatory tachycardia, and tachypnoe. The hypoperfu-
clinical findings however depend strongly on the underlying sion in the systemic circulation occurs as a cardinal symptom
disease. There are several physiological circumstances which in left ventricle dysfunction due to the impaired CO, and leads
may result in a hyperdynamic state, such as stress/anxiety, to renal dysfunction or malabsorption followed by cardiac
physical exercise, pregnancy, or fever (Table 5). 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
Unilateral heart failure: Right-sided versus left-sided cardiac decompensations and/or multiple organ dysfunction.
heart failure The cardinal symptoms of heart failure are unspecific, mul-
Left- and right-sided heart failure are clinically separated syn- tifactorial, and occur often in patients with other underlying
dromes; however, patients often present with a combination causes as well (e.g., pulmonary artery embolism). They can
of left- and right-sided hear failure, what is called global con- be observed during physical exertion in early stages, but later
gestive heart failure. This close relationship occurs due to at rest as well. Not only heart failure incidence increases with
the interdependence of the two connected circulatory systems age, but that of concomitant comorbidities, such as anemia,
of the heart: the systemic, “left” and the pulmonary, “right” renal failure, or depression as well. These may be causally
circulatory system. In left-sided cardiac dysfunction the heart associated or independent from the heart failure itself, but
fails to maintain a continuous peripheral tissue perfusion with have a great impact on the severity of the disease and on
the required amount of blood. Not only the amount of blood prognosis. The activated compensatory pathophysiological
volume is reduced, also the distribution changes. Thus com- systems in heart failure affect mainly the myocardium, but
pensatory mechanisms occur, for instance, the utilization of lungs, kidneys, gastrointestinal tract, or peripheral vascular
oxygen from the blood increases. The heart tries to com- system as well. In general, heart failure is a systemic disease
pensate with an increased filling, thus systolic and diastolic and affects all organ systems in the human body. Its signs and
pressure in the left atrium rises, causing an elevated pressure symptoms are often uniform, but the underlying pathophys-
status in the pulmonary circulatory system. The pressure- iology can be quite diverse. Therefore, its treatment needs a
induced fluid-leakage from the capillaries leads to chronic holistic approach, taking into account different etiologies.
pulmonary congestion. The juxta-alveolar tension receptors
become also activated and the elastic resistance increases, Pulmonary manifestations
leading to the well-known symptoms and signs of left-sided
Pulmonary congestion
heart failure. The reflex-tachycardia may, in contrast, lead to
a vicious circle by additionally reducing the ability of the Due to the increased alveolar capillary pressure, fluid
heart to contract effectively. Right-sided heart failure is char- transudation and accumulation develops in the pulmonary
acterized by a reduced blood supply mainly in the pulmonary interstitium and perialveolar space, and pulmonary crackles

or crepitations can be auscultated on the basis of the lungs. In the central insensitivity—arterial PO2 falls and PCO2 rises in
mild heart failure, the induced lymphatic drainage transports arterial blood gases. This constellation stimulates the central
the alveolar and interstitial fluid back to the venous side of regulatory center and is followed by a compensatory phase
the systemic circulation, but this compensatory mechanism of hyperventilation and a resulting hypocapnia. Hypocapnia
exhausts over time. The congestion activates furthermore induces an apneic phase again, triggering a new circle (66,89).
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 Cardiac symptoms
pressure results in fluid transudation into the pleural cavity, Heart failure is often accompanied by cardiomegaly, the
nevertheless if crepitations present extensively over both lung enlargement of the heart. It is best seen in chest X-ray, where
fields and are followed by expiratory wheezing, pulmonary the cardiothoracic index is significantly elevated (>50%). In
edema occurs. cardiomegaly, the punctum maximum of the maximal impulse
is usually displaced left-lateral, and may have a prominent pal-
Dyspnea, orthopnea, bendopnea, and paroxysmal pable pulsation. The first heart sound is usually soft, especially
if the patient is tachycardic. A third (94) or even fourth heart
nocturnal dyspnea
sound or protodiastolic gallop may also present in patients
Besides pulmonary congestion, there are other factors, which with heart failure. It is best audible at the apex and occurs
may also induce and affect cardiac dyspnea, for instance ane- mostly in volume overload. Moreover, murmurs of mitral or
mia, increased pulmonary resistance, and diaphragm and/or tricuspid regurgitation may be auscultated.
respiratory muscle fatigue. If dyspnea occurs in a recumbent
position, it is called orthopnea, and results from the redis-
tribution of fluid from the lower extremities and splanchnic Vascular signs
circulation into the cardiopulmonary circulation. Orthopnea Vasculature
may present more explicit by extreme obese patients or by
patients with ascites or known pulmonary disease. It is usu- The regulation of the vascular tone and thereby the adaptation
ally relieved by sitting up or in a forward-leaning position. to several mechanical changes and altered pathophysiologi-
Novel form of dyspnea has been recently characterized: in cal circumstances are regulated by the vascular endothelium.
bendopnea, shortness of breath occurs when bending forward, The elevated peripheral resistance or afterload in heart failure
as a sign of excessive fluid retention. It is mediated via acutely leads to activation of the neurohormonal system, such as to
elevated filling pressure in an already increased pressure state, increased production of vasoactive molecules, in which the
especially if the cardiac index is reduced (119). Pulmonary vascular endothelium plays an important role.
nocturnal dyspnoea and nocturnal cough refer to the state
when short periods of severe dyspnoea and coughing, wheez- Jugular veins
ing attacks occur during the night. It may develop due to an
increased pressure in the bronchial arteries that leads to com- The filling of the jugular veins represents the right atrial pres-
pression in the airways, or because of increased pulmonary sure. It can be examined in a half-lying half-sitting position
resistance by congestion. It is usually characterized by per- in 45 grades, with the head looking to the other side of the
sistent wheezing; coughing without any relieving positions or examined vein. It is expressed in centimeters of water, and
maneuvers. 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 abdominojugu-
Cardiac asthma lar or hepatojugular reflux sign and defined by a significantly
The most severe manifestation of acute congestive heart fail- increased jugular venous pressure (>12 cmH2 O) for at least
ure is cardiac asthma. It is characterized by severe wheez- 15 s after abdominal (mainly in the liver region applied) pres-
ing, coughing, and dyspnea due to progressive bronchospasm. sure. Phlebectasia of the internal jugular vein can also occur
Bronchospasm is thought to occur as a combination of ele- in other conditions as well, for instance, in tricuspid stenosis,
vated bronchial and pulmonary vascular pressure, narrowed constrictive pericarditis, superior vena cava obstruction, or
airways by reduced lung volume, and obstruction from intra- cardiac tamponade.
luminal edema (68).
Anemia
Cheyne-Stokes respiration
Heart failure increases both the incidence and prevalence
The periodic Cheyne-Stokes respiration occurs typically in of—usually moderate—anemia (8), in NYHA class II to
advanced heart failure, and is caused by the PCO2 insensitiv- III the prevalence of anemia makes up about 20%. Con-
ity or depression of the respiratory center. The cycles of the comitant anemia is common especially in women, elderly
respiration are made up of an apneic phase, in which—due to patients, or patients with renal failure (117). The causes

include decreased vitamin, iron, etc. absorption due to car- often causes decreased renal filtration rate by reduced blood
diac congestion, increased blood loss by an anticoagulative flow, and through neurohumoral hyperactivity an impaired
therapy, or chronic inflammation. Due to the existing ane- renal function. Therefore it is difficult to differentiate, what
mia, oxygen transport, and/or oxygen utilization is depressed came first: heart failure (cardiorenal syndrome) or renal
in tissues, which significantly reduces the physical capacity. parenchymal disease causing cardiac dysfunction (renocar-
According to the latest studies, iron supplementation appears dial syndrome) (107). It should be acknowledged that there
to have a positive impact on anemia (FAIR-HF), in contrast, is an overlap between these two syndromes. Cardiorenal
a pure anemia correction seems to be less promising; a final syndrome occurs as a result of multiple mechanisms, some
judgment however, will depend on the results of currently of them connected directly to heart failure (perfusion loss
ongoing clinical trials (RED-HF, STAMINA-HeFT). and impaired baroreceptor control) (4) and partially to risk
factors (hypertension), or to pharmacotherapy (diuretics and
ACE inhibitors) of heart failure. The mechanisms underlying
Extremities
the enhancement of cardiovascular mortality by primary
The cardinal manifestation of heart failure is peripheral kidney disease are not well defined. These include uncon-
edema. It occurs usually symmetric in the lower extremities trolled hypertension, inflammation, myocardial and vascular
(ankles and pretibial), or may present presacral or scrotal in calcification, and oxidative stress. Renal function disorder
bedridden patients. It is usually accompanied by skin pigmen- is also thought to contribute and is connected to anemia in
tation and induration over time, but disappears after diuretic heart failure. Therefore, the validity of the—partially renal
therapy. Not only cardiac, but peripheral muscles react to eliminated—heart failure marker BNP (B-type natriuretic
heart failure. They respond with muscle mass reduction, reor- peptide) and its precursor NT-proBNP for the severity of
ganized muscle structure, and altered metabolic functions. heart failure is reduced in renal failure (71, 129).
Furthermore, the extremities are often cold and pale; the acres
are cyanotic due to the vasoconstriction and centralization.
Cerebral symptoms
Cerebral symptoms such as confusion, sleep disorders, dizzi-
Gastrointestinal symptoms
ness, altered mood, or disorientation occur often in patients
Patients with advanced heart failure may also suffer from gas- with heart failure, especially in elderly. The term “cardio-
trointestinal problems. Systemic congestion—including the genic dementia” identifies the link between impaired cog-
bowels or the liver—is often accompanied by anorexia, nau- nitive function and cardiac dysfunction (28). This associa-
sea, or abdominal pain. In hepatomegaly, the congested liver is tion with heart failure is a consequence of the shared risk
not only enlarged, but also often tender, even painful, and pul- factors, perfusion abnormalities, and rheological alterations.
sating (12). As a result of the elevated hepatic vein pressure, There are two main manifestations of impaired cerebral func-
ascites usually occurs. As a late sign, jaundice may develop, tion (ICF): acute and fluctuating, known as delirium, which
resulting from altered liver function, congestion, and from can be precipitated by an underlying medical illness; and
hypoxia due to impaired perfusion. chronic ICF mostly by stable heart failure. Some border zone
manifestations are also known, such as the mild cognitive
Cardiac cachexia impairment (MCI) or cognitive impairment but no demen-
tia (CIND). Compared with the general population, depres-
Patients with advanced heart failure usually have peripheral
sion is up to five times more common in patients with diag-
muscle wasting, which is often restricted to the lower limbs
nosed heart failure. Depression increases significantly mor-
(disuse atrophy) or affects the whole body and other tissues
bidity and mortality and causes a major decrease in quality
as well, called cardiac cachexia (10). The exact mechanism of
of life (43). The negative impact of depression on the course
cardiac cachexia, one of the severe manifestations of advanced
of the disease is multifactorial and cannot be attributed only
heart failure, is not known, but there are some mechanisms
to “impaired health behavior.” Indeed heart failure itself may
which affect its development. Increased metabolic rate, nau-
influence other pathophysiological factors, like imbalance of
sea, vomiting, anorexia, malabsorption due to abdominal and
the autonomic nervous system or inflammatory processes that
liver congestion, and induced proinflammatory processes are
secondary cause depression. In addition to psychotherapeutic
certainly involved. Cardiac cachexia is associated with poor
treatments, antidepressants provide a therapeutic option, even
prognosis of the disease.
though many agents are contraindicated due to their potential
proarrhythmic effects (95). The benefit of these antidepres-
Renal failure sants is still unclear; results of clinical trials are pending.
Renal failure is an independent risk factor for heart failure,
which strongly influences the clinical outcome of the disease. Development of Heart Failure
An increased salt and fluid retention by impaired renal
function often leads to elevated filling pressure and systemic During the development of heart failure, a complex network
volume overload. Vice versa, low-output cardiac failure of compensatory mechanisms is activated on macro- and

microstructural, cellular, and molecular levels to maintain Table 6 Shift along the Frank-Starling Curve and Its Causes
heart function. The most important parts of this network
include the stretch-induced increase of the cardiac preload by Right Left Isolated
the Frank-Starling mechanism, activation of different neuro-
hormonal pathways, and structural changes in the myocardial Upward – Treatment with Isolated diastolic
architecture. Independently of the underlying cause, a con- positive inotrope dysfunction
served compensatory pattern occurs in heart failure. These Downward Depressed – Decreased
mechanisms are, however, influenced by several, noncontrol- contractility contractility
lable factors such as age, gender, or genetic background. The increased
afterload
compensatory mechanisms and the results of their exhaustion
are listed in Table 5. Isolated Increased –
cardiac
performance
Basic concepts
At the end of diastolic ventricular filling, myocytes reach their which explains the pathophysiologic adaptation of the ventri-
maximal stretch length, which is determined by myocardial cle. There is actually a shift along the standard curve, which
compliance, the filling volume, and the resting force. The is defined by the afterload and inotropic state of the heart. A
distending force or filling volume, which occurs in this sta- plateau in the Frank-Starling curve may also develop in cer-
tus, is the preload. Preload can be calculated as: preload = tain cases, if the heart simply reaches its maximum capacity to
(LVEDP×LVEDR)/2h, where LVEDP is the left ventricular increase its contractility in response to increasing stretch. The
end-diastolic pressure, LVEDR means left ventricular end- plateau in the Frank-Starling curve also represents a reduc-
diastolic radius and “h” represents the left ventricular thick- tion in the heart’s systolic reserve. The changes, shifts in
ness. During ventricular contraction and transmission of the the Frank-Starling curve and their causes are represented in
stroke volume (SV) into the systemic circulation, left ven- Table 6.
tricular 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 reflec- Laplace’s law/Young-Laplace equation
tion, and small vessel resistance (left ventricular afterload) LV wall stress = (LV pressure × radius)∕2xLV wall thickness
or similarly pulmonary artery parameters (right ventricular
afterload). Left ventricular afterload is increased in arterial The Young-Laplace equation describes the capillary pres-
hypertension or aortic stenosis, where the left ventricle has sure difference between two static fluids due to surface/or
to overcome the elevated peripheral resistance and decreased wall tension. In cardiac physiology, the equation defines the
compliance. In contrast, in mitral regurgitation a decreased factors that have an effect on ventricular wall stress. It has a
ventricular afterload occurs. In conclusion, the three deter- great importance in evaluating the actual oxygen demand of
minants of left ventricular function are myocardial contrac- the heart, which is directly proportional to wall stress.
tility, 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 Causes for an elevated ventricular wall stress and
Frank-Starling mechanism and Laplace’s law. therefore increased oxygen demand
r Elevated afterload (increased left ventricular pressure)
Frank-Starling mechanism r Arterial hypertension
The relation between left ventricular pressure and volume r Aortic valve stenosis
is presented in the Frank-Starling curve. It shows that the
major three parameters of cardiac function are venous filling r Systolic heart failure with left ventricular dilation
determining left ventricular end-diastolic volume (preload), (increased left ventricular radius)
peripheral resistance (or afterload), and myocardial contrac-
tility. The ability of the heart to change its contraction force
r Valvular heart diseases
and increase SV due to an elevated preload, is called Frank- r Cardiomyopathies
Starling mechanism. It describes the length (sarcolemma)-
tension (stretching)-force (contractility)-velocity (SV) rela- r Increased left ventricular wall thickness
tion in the heart (42). In which way the myocyte sarcolemma
elongates, is still unclear, but there are some theories like the
r Chronic hypertension
length-dependent reduction in lateral spacing between thick r Aortic valve stenosis
and thin filaments, or calcium-induced cross-bridge attach-
ment and detachment. There is no single Frank-Starling curve,
r Hypertrophic obstructive cardiomyopathy

Pressure-volume loop
160
Normal
Decreased afterload
LV pressure
Increased afterload
(mmHg)
Increased inotropy
Decreased inotropy
80
0
0 ESV 100 EDV 200
LV volume (mL)
Figure 1 PV loop showing the correlation of pressure and volume alterations in

physiological and pathological conditions.
r Decreased left ventricular wall thickness connected vessel, the aorta, or pulmonary artery, respec-
r Myocardial infarction tively.
dP/dtmin and dP/dtmax : These parameters define the minimum

Pressure-volume loop and maximum rate of ventricular pressure changes.
The Frank-Starling curve does not show the influence of
venous return on end-diastolic and end-systolic volume. Tau: Tau shows the exponential decay of pressure during
Therefore ventricular function should be described in terms isovolumetric relaxation in the ventricles. Calculation of
of pressure-volume (PV) diagrams. The PV curve represents Tau is performed by the Glantz method: P(t)= P0e-t/τE +
the pressure and volume changes during the heart cycle. For Pα, where P defines pressure at time point “t,” P0 shows
instance, when the venous return increases, the diastolic fill- amplitude constant, τE is the Glantz relaxation constant,
ing of the ventricle elevates the ventricle’s passive pressure, and Pα means non zero asymptote.
leading to an increased end-diastolic volume. If the ventricle
contracts with this preload and constant afterload, the ven- Arterial elastance (Ea): Ea represents the arterial load and
tricle will empty to the same end-systolic volume, thereby is defined as the ratio of ventricular end-systolic pressure
increasing its SV. Afterload alterations as well as valve dys- and SV.
functions can also be presented in the PV curve. Alterations
in cardiac inotropy and afterload with their hemodynamic End-systolic pressure volume relationship (ESPVR): ESPVR
effects are shown in Figure 1. For the complete and clear represents the maximal pressure at a given volume that can
understanding of the PV loops, the following hemodynamic be reached by the ventricle. The slope of ESPVR represents
parameters should be defined: the end-systolic elastance, which is an index of myocardial
contractility. It becomes steeper and shifts to the left as
Stroke volume (SV): SV is the ejected blood volume from the contractility increases and becomes flatter and shifts to the
right/left ventricle in a single contraction. It can also be right as inotropy decreases, respectively.
defined as the difference between the end-diastolic and the
end-systolic volume. End-diastolic pressure volume relationship (EDPVR):
EDPVR describes the passive ventricular filling curve. The
Ejection fraction (EF): EF is the fraction of end-diastolic slope of the EDPVR defines the ventricular stiffness.
volume that is ejected out of the ventricle during each
contraction. Pressure-volume area (PVA): PVA shows the total ventricular
contraction energy.
Cardiac output (CO): CO is defined as the amount of blood
pumped by the ventricle per defined unit time.
Remodeling in heart failure
Stroke work (SW): The ventricular SW represents the work The term remodeling is used to summarize the structural and
performed by the left/right ventricle to eject the SV into the subsequent functional changes in the heart after injury. It

subsumes alterations in heart dimensions, mass, and shape Reverse remodeling

in response to a specific cardiac event (41, 61). Remod-
eling can be divided into physiologic/pathologic or adap- The term left ventricular reverse remodeling (LVRR) refers
tive/maladaptive. Physiologic remodeling is called “athlete’s to the improvement of the cardiac function after the complete
heart” (78), when the remodeling occurs after physiologi- development of heart failure, due to compensatory mecha-
cal stimuli. It is clearly different to pathologic remodeling. nisms (101). It describes a broad spectrum of beneficial phys-
For example, there is no pathologic fibrosis. The molec- iological alterations in the heart resulting in myocardial recov-
ular mechanisms are unclear but might involve IGF sig- ery. Structurally it is defined by reduced ventricular chamber
naling. Pathological remodeling develops if the underlying volumes and pronounced sphericity. It is characterized by
cause is a pathological process, for example, cardiac injury, an improved β-adrenergic sensitivity and therefore by bet-
pressure, or volume overload. Independently of the under- ter heart-rate responsiveness. Furthermore, it is associated
lying pathologic cause, cardiac remodeling has a common with a decline in inflammatory mediators, such as IL-1, IL-8,
molecular, biochemical, mechanical pathway, and involves or TNFα. On a molecular level, reverse remodeling impacts
all cells and components of the entire heart: cardiomyocytes, on myocyte size, function, excitation-contraction coupling,
fibroblasts, endothelium, and the interstitium (58). There bioenergetics, and a host of molecular pathways that regu-
are several modifying factors that have an effect on car- late contraction, cell survival, mitochondrial function, oxida-
diac remodeling, such as activation of the neurohumoral sys- tive stress, and several other features. Reverse remodeling
tem, blood pressure, or the hemodynamic changes in heart has already successfully been achieved by pharmacother-
chambers. The main macrostructural characteristics of car- apy such as by renin-angiotensin-aldosterone system (RAAS)
diac remodeling are ventricular hypertrophy and dilation due inhibitors or β-blockers, and by interventional-surgical ther-
to cardiomyocyte reorganization and elongation, increased apy approaches like cardiac resynchronization therapy or the
ventricle wall tension, and impaired subendocardial perfu- implantation of left- or biventricular assist devices (5, 115).
sion. Cardiac remodeling is accompanied by several cellular There are numerous clinical and imaging factors, which can
changes, such as cardiomyocyte hypertrophy, myocyte apop- predict LVRR, inter alia 2D-echocardiographic parameters,
tosis and necrosis, fibroblast proliferation, accumulation of such as left ventricular end-systolic volume or strain imaging,
proinflammatory mediators, and extracellular matrix reorga- which is able to identify global and regional left ventricular
nization characterized by fibrosis induction. Progression of function, scar burden, or myocardial viability (21, 97).
cardiac remodeling is influenced by many factors, including
the severity of the causing event, possible secondary events,
adaptive compensating mechanisms, adverse reactions, and Architectural changes in heart failure
the efficacy of the treatment. There is no exact time point
Microstructural changes
when the transition from possible adaptive to maladaptive
remodeling occurs or how this could be identified (Table 7). Cardiomyocyte hypertrophy, apoptosis, and necro-
sis The first and most important responses to chronic pres-
sure and/or volume overload of the heart include hypertro-
phy of cardiomyocytes, accelerated apoptosis-regeneration
Table 7 Summary of Cardiac and Vascular Architectural and Func-
tional Changes circle of cells and remodeling of the myocardial structure.
Myocardial injury sets into motion several signaling pathways
Architectural Functional
on the molecular level resulting in adaptive reactions. Due
to the activation of the neurohormonal cascades, vasoactive
Cardiac Ventricular dilation Decreased SV and CO
components (angiotensin II, endothelin-1, or vasopressin) are
released. The following vasoconstriction increases the cellular
Ventricular hypertrophy Increased end-diastolic
pressure
calcium concentration in cardiomyocytes via calcium preload,
afterload, and the induction of cyclic adenosine monophos-
Increased ventricular Impaired filling
stiffness (diastolic dysfunction)
phate (cAMP) formation. The increased intracellular calcium
level has a positive inotrope and a negative lusitrope effect,
Reduced EF (systolic
dysfunction)
thus improves cardiac contractility and decreases myocardial
relaxation. However, an excessive calcium entry into the cells
Vascular Constriction of arteriolar Impaired organ
resistance vessels perfusion and the increased cardiac contractility often leads to malignant
arrhythmias and—in extreme cases—to sudden cardiac death
Increased systemic Increased afterload
vascular resistance (17). The shift to myocyte apoptosis in the strictly balanced
cell turnover (125) causes first a scattered, later a diffuse loss
Increased venous Increased preload
pressure of cardiomyocytes (124).
As a consequence of the slower turnover and maladap-
Decreased venous
compliance tive reactions of the cardiomyocytes, the presenting pressure
and/or volume overload affects the remaining intact myocytes

and therefore puts greater pressure on them. It also concerns is thought to be the mediator of cardiac remodeling after
the myocyte progenitor cells, leading to an impaired turnover myocardial infarction (48). MMP-9 deleted mice had less
(3, 62). This processes result in decreased ventricular con- collagen accumulation and fibrosis and less ventricular dila-
tractile function and eventually in heart failure over time. tion after myocardial infarction (35). Not only MMPs, but
Cardiomyocyte apoptosis and necrosis occurs predominantly their inhibitors play an important role in heart failure. The
in postinfarction heart failure, but presents in all other forms most dominant and specific inhibitors are the family of tissue
of heart failure as well. inhibitors of metalloproteinases (TIMP 1-4). The extracellu-
lar matrix is a dynamically changing, reorganizing, “living
system” with a constant turnover of its components. The bal-
Interstitial fibrosis
ance of MMPs and the TIMPs maintain the homeostasis of
The cardiac interstitium is made up of three different compo- the interstitial architecture.
nents: the endomysium, the perimysium, and the epimysium.
The endomysium surrounds single cardiomyocytes, the per-
Macrostructural changes
imysium groups of myocytes, and the epimysium envelops
the chambers of the heart. It gives a basic framework for Left ventricular hypertrophy The primary architec-
cellular components, maintains normal tissue tensile strength tural characteristics of cardiac remodeling are the measures
and stiffness, and transmits the myocyte-generated contrac- of left ventricular mass, volume, and their interrelationship,
tile force. Furthermore, it also plays part in myocardial home- resulting from the cardiomyocyte reorganization pattern (69).
ostasis by providing a surface for different processes, such A classification system involving these parameters has been
as cell migration, differentiation, proliferation, or signaling established by the American Heart Association. It defines car-
pathways. It regulates fibroblast metabolism and turnover diac remodeling on the basis of M-mode echocardiographic
(39, 130). measurements as an elevated left ventricle mass >115 g/m2 in
Heart failure is accompanied by the progressive accu- men and >95 g/m2 in women, or as a relative wall thickness
mulation of interstitial collagen fibers, which decrease the (RWT) of >0.42. From this categorization, three different
myocardial contractility and compliance, and therefore cause macrostructural responses to cardiac injury can be defined:
ventricular systolic and/or diastolic dysfunction (106). The concentric (increased LV mass, increased RWT), eccentric
exact mechanism of these fibrotic changes is still unclear, but (increased LV mass, normal RWT), and combined concentric-
there are two main theories. First, it is thought that a reac- eccentric hypertrophy (23, 31). Eccentric hypertrophy can be
tive collagen fiber accumulation occurs in the interstitium further divided into three different subtypes according to the
and perivascular regions and leads to fibrotic changes. On the origin of the structural reorganization (Fig. 2).
other hand, an adaptive, reparative fibrosis due to myocyte Concentric hypertrophy occurs after pressure overload of
loss is suspected. Not only the amount of the cardiac col- the heart, for example, by arterial hypertension or aortic steno-
lagen changes in heart failure, but also the quality with a sis. It presents with or without an increase of the myocardial
shift from insoluble to soluble collagen, leading to reduced mass and is characterized by increased wall thickness with
myocardial cross-linking and therefore an impaired ventricu- parallel organized sarcomeres and myocyte thickening. The
lar contraction. The formed fibrotic tissue is a dynamic struc- diastolic PV curve shifts to the left along the volume axis. Fur-
ture, metabolically active, contractile, and is able to adapt to thermore, the ventricular diastolic pressure elevates without a
changing circumstances. Due to interstitial fibrosis, the capil- significant increase in the ventricle stiffness.
lary density also reduces, which results in an impaired oxygen Eccentric hypertrophy due to physiological stimu-
supply of the tissues and therefore hypoxia-induced structural lus/athlete’s heart syndrome/AHS is a physiological adap-
changes and apoptosis/necrosis of the cells. tive condition presenting in young sportsmen—commonly
Collagen turnover of the heart is regulated by several fac- in endurance athletes—with relevant sinus bradycardia,
tors. Collagen synthesis is induced by growth factors, like exercise-induced cardiomegaly, and eccentric cardiac hyper-
TGFβ (67), PDGF, FGF, by different cytokines, such as IL-1, trophy with increased CO. AHS is generally considered
IL-4 (54), tumor necrosis factor α (TNFα) and also by hor- benign, it does not affect the overall survival, but it is crucially
mones and some different regulating factors like aldosterone, important to differentiate it from hypertrophic cardiomyopa-
angiotensin II (131), or endothelin. The degradation of the thy, a genetic heart disorder, which is a leading cause of
extracellular matrix collagens is controlled by matrix metal- sudden cardiac death in young athletes (77, 79).
loproteinases (MMPs). The main function of MMPs is the Eccentric ventricle structure reorganization after volume
support of tissue remodeling, which occurs in several physi- overload (e.g., severe mitral regurge) results in increased car-
ological (morphogenesis) and also pathological (metastasis) diac mass and chamber volume. The changes in ventricle
conditions. In the heart, they present under physiological con- wall thickness depend on the mechanism; it can be normal,
ditions in an inactive form in the ventricle, and become acti- increased, and decreased as well. Sarcomeres are organized in
vated after myocardial injury. The activation of the MMPs longitudinal series. Over time, wall-thinning develops and the
leads to collagen degradation and thereby increased cham- heart geometry takes up a more spherical shape, associated to
ber dimensions and reduced SV (34). For instance, MMP-9 a continuous decline in left ventricular EF.

Normal Physiological state Physiological myocardial mass, diameter,

wall thickness
Concentric Arterial hypertension Increased wall thickness

Aortic stenosis Normal/ increased myocardial mass
Parallel organized sarcomeres
Eccentric Mitral valve regurge Increased mass

Dilative cardiomyopathy 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) efficiency becomes impaired, and leads to heart failure. Not
results from a specific damage to the myocardium, which only the ventricles but the atria may also respond with cham-
occur by metabolic, infectious, or toxic agents. The deterio- ber dilation to chronic volume overload (e.g., in mitral valve
ration of the cardiac function is more rapid than in any other regurge). In conclusion, a more spherical shape of the heart by
forms of eccentric hypertrophy, caused by frequent concomi- progressive dilation generates numerous pathological, struc-
tant regional wall motion abnormalities and heart valve dys- tural alterations, such as mitral insufficiency with regurgita-
function. tion by pulled-away papillary muscles.
Combined concentric/eccentric left ventricle remodeling
presents, for example, after myocardial infarction. Due to the Left ventricular stiffness, compliance
infarcted, fibrotic tissue, dilation develops in the nonfunc-
tioning area, and increased pressure occurs in the functioning Left ventricular stiffness is defined by the relationship
areas and causes concentric hypertrophic changes. between ventricular pressure and volume, as the passive
change in volume divided by the associated change in pres-
sure (135). Increased left ventricle stiffness occurs as result
Ventricular dilation
of many influencing factors, such as elevated filling pressure,
Ventricular dilation may occur in response to three different decreased distensibility, and steeper curve of the ventricu-
cardiac injuries: hypervolemia by impaired renal or cardiac lar PV ratio (110, 133). A rise in filling pressure occurs under
function, volume overload, for example, by aortic or mitral pathological conditions such as volume overload secondary to
regurgitation, or in dilated cardiomyopathy (idiopathic, alco- acute valvular regurgitation. Decreased distensibility is char-
holic, etc.). In ventricle dilation, new myocardial sarcomeres acteristic in extrinsic compression of the ventricles. A shift
are added sequentially to preexisting sarcomeres. The mod- to a steeper curve of the ventricular PV ratio results most
ified structure first increases the ventricular compliance, but commonly from increased ventricular mass and wall thick-
over time the ventricular wall stress rises, and impaired oxy- ness, for example, in aortic stenosis, or hypertension, and
gen supply occurs. The heart’s mechanical and functional also from infiltrative disorders, for example, amyloidosis (40).

Ventricular compliance is the ability of the heart chamber to Table 8 Biomarkers in Heart Failure
distend and elevate the transmural pressure to increase its
volume. Neurohormones Norepinephrine (NE)
Renin
Angiotensin II (AT-II)
Activation of the Neurohumoral System Aldosterone
The first activated system in response to impaired cardiac Arginine vasopressin/ADH
function is the neurohumoral system, which includes the ET-1
sympathetic nervous system, the RAAS and vasoactive pep-
Myocyte strain Natriuretic peptides: BNP, NT pro-BNP,
tides. In heart failure, the pressure-baroreceptors are activated specific molecules ANP
in the carotid sinus, aortic arch, and in the left ventricle. The
Adrenomedullin
afferent signals modify the central cardioregulatory centers
to increase the circulating blood volume. Sympathetic and Cotransport inhibitory factor (CIF)
humoral efferent mechanisms are stimulated, and the antidi- Growth-differentiation factor-15 (GDF-15)
uretic hormone arginine vasopressin is released from the pos- ST2
terior pituitary gland. Sympathetic activation of peripheral
Apelin
organs, for example, kidney, vasculature, skeletal muscles,
or the heart itself results in perfusion redistribution. Further- Bradykinin
more, constant neurohumoral activation leads to transcrip- Urotensin II
tional and posttranscriptional changes in the genome, espe- Cardiac injury Cardiac Troponins: Troponin T, Troponin I
cially by genes regulating the structure and mechanics of induced peptides
cardiomyocytes. There are also several biomarkers involved Creatine kinase with/without MB-fraction
(CK+/-MB)
in the adaptive processes, listed in Table 8.
Myosin light-chain kinase I
Heart-type fatty-acid protein
Sympathetic nervous system Proinflammatory CRP
The activation of the systemic and cardiac sympathetic mediators
nervous system is the fastest adaptive response mechanism Cytokines: TNFα, IL-6
in heart failure (65). The sympathetic nervous system is Chemokines: MCP-2, IL-8, NAP-2, GRO-α
activated by pressure-sensitive (baro-) receptors. Under Fas (APO-1)
physiological circumstances, “high-pressure” baroreceptors Oxidative stress Myeloperoxidase
in the carotid sinus and aortic arch, and “low-pressure” components
baroreceptors, located in the walls of major veins and in Xanthine oxidase and uric acid
the right atrium of the heart, are the main inhibitors of Allantoin
the sympathetic nervous system. In contrast, the peripheral Oxidized LDL
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 α1-receptors will also be stimulated with the result of an
impulses increase. This generalized sympathetic activation increased peripheral vascular tone and positive inotropy
with concomitant parasympathetic decrease is followed (52, 91).
by impaired heart rate variability, elevated blood pressure, The sympathetic activation has some negative effects as
and increased peripheral resistance. It results in a positive well: the release of catecholamines can potentiate differ-
inotropic (increased contractility) and chronotropic (tachy- ent arrhythmias and may aggravate myocardial ischemia.
cardia) effect, which cause blood redistribution by peripheral Furthermore, plasma epinephrines are also well-known
vasoconstriction and central vasodilation to maintain the per- directly toxic to cardiac myocytes and induce their hypertro-
fusion of vital organs. It activates the RAAS that controls the phy and apoptosis as well. Moreover, norepinephrine causes
salt-fluid homeostasis and arterial blood tension. The plasma different signal-transduction abnormalities, like the down-
noradrenalin level rises, which correlates with mortality in regulation of β1- or uncoupling of β2-adrenergic recep-
patients with advanced heart failure (111). However, in severe tors. The activation of the β1-receptors cannot only induce
heart failure, the plasma noradrenaline level and myocardial reflectory tachycardia but malignant ventricular arrhyth-
tyrosine-hydroxylase decrease significantly, possibly due to mias too. The maladaptive systemic and regional vasocon-
exhaustion after prolonged activation in the course of the striction leads further to different organ failures, such as
disease. Besides β1-adrenergic activation, the myocardial renal failure, pulmonary hypertension, etc. The decreased

Table 9 Biological Effects of Activated Cardiac Adrenergic Receptors activity of the parasympathetic nervous system results in
abnormal autonomic modulation and reduced heart rate vari-
Adrenergic ability. The activation of the sympathetic nervous system can
receptor Beneficial effect Harmful effect have beneficial effects by the adaptation to altered physio-
logical circumstances but may also be harmful. (Listed in
α1c Positive inotropy Myocyte damage Table 9.)
Proarrhythmic Beta-adrenergic signaling pathways play a pivotal role
in cardiac function and dysfunction (73). Cardiomyocytes
Vasoconstriction
express all β-adrenergic receptor subtypes; β-receptors
β1 Positive inotropy Myocyte damage, are also expressed in nonmyocyte cells [endothelial cells
apoptosis
and fibroblasts (60)]. In heart failure, the sympathetic
Positive chronotropy Fetal gene induction
signaling pathways are activated and cardiac beta receptor
Vasodilation Proarrhythmic number, density, and activity are reduced with decreased
(epicardial)
catecholamine sensitivity (22) Gsα and adenylyl-cyclase
Positive lusitropy (51) become downregulated, which are part of rate limiting
β2 Positive inotropy Proarrhythmic steps in the signaling pathway. These alterations can be
Positive chronotropy Fibroblast hyperplasia
interpreted as compensatory protecting effects, which
save the cardiac reserves by protecting from arrhythmias,
Vasodilation (small
vessel)
apoptosis, and cardiac hypertrophy; however, they may
also lead to functional deterioration by energy starvation.
Antiapoptotic
Further contributing factors are the GRKs (15), which
Positive lusitropy are significantly upregulated and activated in heart failure
(123, 138) Figure 3 shows beta receptor signaling pathways
in the heart with modulated targets and functional effects.
β2AR β1AR
AC
Ca2+
Gi Gs Gs Ca2+
ATP cAMP
SERCA
p
PKA Ph
P13K PLA2 Src CREB Troponin I RyR CaMKII
Ras
Akt Raf
MAPKK
Apoptosis Inotropy Hypertrophy Lusitropy Inotropy Apoptosis
Figure 3 Beta-adrenergic signaling pathways and their effects in the heart.

Renin-angiotensin-aldosterone system activation apoptosis, and causes structural and biochemical alterations
in the extracellular matrix (81, 140). Angiotensin has further-
The activation of the RAAS is pressure-mediated reflex,
more metabolic effects, such as upregulation of tissue lipoge-
which potentiates the prorenin-renin conversion and renin
nesis and reduction of lipolysis, and thereby causes fat mass
release from the macula densa in the juxtaglomerular cells
expansion in the body. Moreover, the induced RAAS often
of the kidney. The macula densa is made up of granular
leads to secondary hyperaldosteronismus (30). The effects
cells, modified pericytes, which lie in the glomerular cap-
of angiotensin II and its further metabolization are shown in
illaries and can release renin into the blood. The plasma
Figure 4.
renin stimulates the transformation of the inactive dekapep-
tide prehormone angiotensinogen to angiotensin I by cleaving
four amino acids. The octapeptide angiotensin I is then con-
verted into angiotensin II by angiotensin-converting enzyme, Further metabolization
released mainly from the pulmonary capillaries. Angiotensin
Angiotensin II may undergo further cleavage producing
II is a vasoactive agent, causing vasoconstriction, blood pres-
angiotensin III [Ang-(2-8)], IV [Ang-(3-8)], and angiotensin
sure elevation, myocyte hypertrophy, myocyte cell death,
(1-7). Angiotensin III is produced by aminopeptidase A, a
myocardial fibrosis, and stimulates the secretion of aldos-
zinc-dependent, membrane-bound enzyme, by cleaving the
terone from the adrenal cortex. The angiotensin II recep-
N-terminal acidic aspartate amino acid (103). Angiotensin
tors are mostly found on the intraglomerular mesangial cells,
III has lower pressure effect than angiotensin II, but induces
causing them to contract and stimulating the adrenal cortex
aldosterone-production the same way and mass. Angiotensin
to release aldosterone. Aldosterone is a hormone, released
IV is a product of the cleavage of angiotensin III by aminopep-
from the zona glomerulosa; its main effect is to increase
tidase N that releases neutral amino acids from the N-terminal
the sodium and water reabsorption from the kidneys into
region. The hexapeptide angiotensin IV has also moderate
the blood. Angiotensin II cannot only be synthesized by the
angiotensin II-like effect. Angiotensin (1-7) is a heptapeptide
RAAS, but also through an independent pathway through a
product of angiotensin II or I by endo- and carboxypepti-
conversion by kallikrein and cathepsin G, or in the tissue
dases, respectively. Its effects counterweigh the vasoactive
through chymase activation (11).
impact of angiotensin II by reversing the pathological pro-
cesses including fibrosis and inflammation. Angiotensin (1-7)
influences tissue metabolism by increasing the glucose uptake
Effects of angiotensin II
and lipolysis, and parallel decreasing insulin resistance and
The major bioactive molecule of the RAAS system with dyslipidemia. It inhibits cell proliferation and angiogenesis;
endocrine, autocrine, paracrine, and intracrine effects is therefore it is thought to be a promising target for cancer
angiotensin II. It has various effects in the whole body and therapy.
induces several pathways to regulate tension and sodium-
fluid regulation. Angiotensin II is a general vasoconstrictor
in all arterioles with a marked effect on the renal efferent
Receptors
arterioles. It stimulates the release of aldosterone, induces
the excretion of noradrenalin from the sympathetic nerve The two major—G-protein receptor associated—receptors
terminals (33), and inhibits the vagal tone. As a result, the that mediate the effects of angiotensin II are the angiotensin
intraglomerular pressure and glomerular filtration rises, which type-1 receptor (AT1R) and the angiotensin type-2 receptor
results in decreased hydrostatic and increased oncotic pres- (AT2R) (122). AT1R is expressed mainly in the vasculature,
sure, and therefore an induced sodium and fluid reabsorption kidney, adrenal cortex, lungs, and in the brain, whereas AT2R
into the peritubular capillaries. Sodium reabsorption occurs is located rather in the myocardium, and more usual in the
eventually due to active and passive mechanisms. First, the fetus and neonate (57). In the myocardium, AT1R is found in
decreased perfusion of the vasa recta leads to decreased nerves, but AT2R rather in fibroblasts and in the extracellular
sodium washout. Increased fluid reabsorption by peritubu- matrix. The effects mediated by AT1R include vasoconstric-
lar capillaries increases the passive reabsorption of sodium. tion (due to the activation of the PLC signaling pathway) with
Moreover, the Na+ / H+ -exchangers of the proximal tubules vascular smooth muscle cell proliferation, cell growth, aldos-
and the thick ascending region of Henle-loop are stimulated terone synthesis and secretion, vasopressin secretion, and cat-
by angiotensin II and reabsorb sodium. Finally, the hypertro- echolamine release. It leads to decreased renal blood flow and
phy of other renal tubular cells through angiotensin II leads to renal renin inhibition as a negative feedback. AT2R activation
sodium reabsorption. Angiotensin II is not only a vasoactive results in vasodilation, natriuresis, and bradykinin release. It
hormone, it has also been shown that cardiac angiotensin II has inhibits cell growth and differentiation. There are also other,
local positive inotropic, negative lusitropic effect on the heart, still incomplete characterized subtypes of angiotensin recep-
and increases the afterload that elevates further the energy tors, namely, the AT3 and AT4 receptors (26). The distribution
expenditures of the heart. Angiotensin II has also a direct and functions of the angiotensin receptors AT1R and AT2R
effect on cardiomyocytes: it promotes hypertrophy, myocyte are listed in Table 10.

Angiotensinogen
Renin
Angiotensin I
ACE
Angiotensin 1-7 Angiotensin II
ACE 2
Further
Effects AT1 AT2 AT3+AT4 Adrenal
metabolization
APA Vascoconstriction NO Laminin
Hypertrophy Antiproliferation ↓PAI-1 Aldosterone
Angiotensin III Proliferation Vasodilation ↑ NO
↑ Na+ retention Anti-inflammation ↓ ET
APN ↑ Oxidation Antioxidative ↓ TIMP-1
Inflammation
Angiotensin IV Thrombosis
Heart Kidney Other effects

(endothelial
Interst Salt and dysfunction,
Fibrosy fluid retention platelet
K+ secretion aggregation,
etc.)
Heart Congestion,
Failure electrolyte
imbalance
Figure 4 Major effects and further metabolization of angiotensin II.
ADH/antidiuretic hormone/arginine vasopressin overload by activated V2 receptors contribute to ventricular

remodeling and dysfunction by exacerbating the diastolic wall
The plasma concentration of the antidiuretic hormone or vaso- stress.
pressin 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 stimula-
tion of the carotid sinus and aortic arch baroreceptors. It con- Natriuretic peptides
tributes to increased afterload and volume overload due to As a mild cardiac dysfunction develops to congestive heart
fluid retention by increased intake and reabsorption from the failure, a relative imbalance occurs in the endogenous
collecting tubules (44). The combination of decreased water vasoconstrictor-vasodilator regulation of the vessels, for the
excretion and increased water intake often leads to fall of benefit of vasoconstriction. The concentration of the vasodila-
plasma sodium concentration. Clinical hyponatremia repre- tive nitric oxide, bradykinin, and natriuretic peptides declines,
sents an important prognostic factor in heart failure. Vaso- whereas vasoconstrictive agents increase their plasma con-
pressin acts on three different G-protein-coupled receptor centrations. Natriuretic peptides are endogenous peptide hor-
subtypes, V1A , V1B , and V2 (18). The V1A receptor is found mones, which are released from the heart chambers as a
on vascular smooth muscle cells and cardiomyocytes. These response of cardiomyocytes to myocardial stretch due to vol-
receptors activate the inositol triphosphate pathway and cause ume or pressure overload. They promote vasodilation and
increased intracellular calcium concentration. The activated natriuresis, so the atrial/ventricular filling decreases, and the
calcium signaling results in vasoconstriction, increased sys- subsequent reduction in preload reverses, or at least slows
temic vascular resistance, and positive inotropy, but leads to down cardiac remodeling. Additionally, BNP (brain natri-
reverse remodeling and progressive heart failure by sustained uretic peptide) inhibits the RAAS (104) and the adrener-
activation. Moreover, it also potentiates the synthesis of con- gic activation. As important members of the compensatory
tractile proteins in myocytes. The renal effects of vasopressin, mechanisms in heart failure, the concentration of natriuretic
such as the upregulation of the aquaporin-2 water channels, peptides has both diagnostic and prognostic relevance (59,
are mediated mainly by the V2 receptor. Chronic volume 75). Plasma ANP (atrial natriuretic peptide) levels rise in the

Table 10 Distribution and Function of the AT1R and AT2R Table 11 Natriuretic Peptide Concentrations in Different Conditions
AT1R AT2R Elevated plasma Low plasma natriuretic

natriuretic peptides peptides
Distribution Adrenals Adrenals
Conditions Ischemic heart Pulmonary edema
Blood vessels Uterus
with heart diseases
Brain Brain failure
Cardiomyopathies Acute mitral
Kidney Kidney regurgitation
Heart (nerves) Heart (fibroblasts, Hypertensive heart Mitral stenosis

interstitium) disease
Liver Fetal, neonatal tissues Hyperthyreosis Left cardiac tumors
Lung Cardiac amyloidosis Constrictive

pericarditis
Prostate
Peri-/myocarditis Cardiac tamponade
Function Vasoconstriction Vasodilation
Obesity
Cell growth, Antiproliferation,
proliferation apoptosis Conditions Advanced age Pulmonary
without heart hypertension
Elevated heart rate Differentiation, failure
development Acute coronary Aortic aneurysm
syndrome
Increased contractility Antidiuresis
Acute pulmonary
Increased renal tubular Renal Na+ excretion embolism
reabsorption
Acute respiratory
Increased aldosterone Dilation of the afferent distress syndrome
release arteriole
High-output states
Sympathetic Increased renin release
hyperactivity Renal failure
Increased vasopressin Increased NO release Atrial tachyarrhythmia

release
ACTH release Bradykinin production
targets involve pro- and anti-inflammatory cytokines, endo-

toxins, adhesion molecules, and chemokines (13).
early phase of the development of heart failure, therefore,
they have been used as marker for the diagnosis of asymp-
tomatic left ventricular dysfunction (80). Dysregulation of Cytokines
the natriuretic peptide system is associated with several car- The concentrations of circulating proinflammatory cytokines
diovascular and noncardiovascular diseases with and with- are significantly increased in heart failure; however, their
out heart failure, summarized in Table 11. The biological exact pathophysiological role, clinical significance and use
effects of natriuretic peptides are mediated by membrane- remain still unclear (109). Cytokines are low molecular
bound natriuretic peptide receptors, NPRs. They activate a weight, biologically active proteins, which act in an autocrine
cyclic guanosine monophosphate-dependent signaling path- or a paracrine manner to modulate cell function. The most
way, which results in vasodilation, increased diuresis with important proinflammatory cytokines involved in heart fail-
natriuresis, and hypotension. Both of them inhibit the RAAS, ure are TNFα, interleukin 1 (IL-1), and 6 (IL-6). These are
endothelin secretion, and the systemic sympathetic activation. secreted from the myocardium and mononuclear cells.
TNFα
Immunomodulation TNFα has a controversial, still not completely understood
The activation of the immune system in cardiac remodeling function in heart physiology. It contributes to the development
came into focus in the past decade. of cardiac dysfunction but is also known for its cardioprotec-
Activation of the innate immune system by so called tive effects (102). Under physiological conditions, the heart
“danger signals” is responsible for inflammatory responses does not produce TNFα, in contrast, after an acute injury the
in heart failure. Inflammatory cells, mediators and their inter- concentration of TNFα raises significantly. Myocyte stretch,
actions have been proven to play a crucial role in the develop- ischemia, pressure, or volume overload are thought to potenti-
ment of heart failure. Therefore, novel pharmacotherapeutical ate TNFα production as well (37). TNFα was found to increase

the expression of antioxidant enzyme manganese superoxide Anti-inflammatory cytokines in heart failure:
dismutase and mitochondrial protein A20, in sense of a pro- IL-10/interleukin-10
tective role in the heart. TNFα is thought to have adverse
effects as well, such as a direct toxicity on cardiomyocytes, Interleukin-10 is a protein homodimer, which is produced by
generation of reactive oxygen intermediates, and thereby the monocytes, type 2 T-helper lymphocytes (TH2), mast cells,
induction of oxidative stress. TNFα is supposed to play a CD4+CD25+Foxp3+ regulatory T cells, and certain subset of
pivotal role in the development of left ventricle dysfunction, B cells. IL-10 downregulates the production of TNFα (112),
remodeling, increased myocyte apoptosis, cardiac cachexia, IL-1 and -6 and reduces the production and release of NO
and endothelial dysfunction as well. There are two different and other reactive oxygen radicals. In contrast, patients with
TNFα cell membrane receptors defined so far, TNFR-1 and chronic heart failure and elevated IL-10 and TNFα-level had
TNFR-2. TNFR-1 is widely expressed and transmits deleteri- significant higher mortality (6).
ous effects of TNFα. TNFR-2 is thought to exert the adaptive,
protective effect in the heart (32).
Chemokines
Chemokines are chemotactic cytokines, small glycoproteins,
which stimulate leukocyte migration, regulate cytokine pro-
Interleukin-1/IL-1 duction, and may induce reactive oxygen species (ROS) for-
IL-1 is made up of two distinct ligands, IL-1α and IL-1β, mation as a response to an acute inflammatory event. There are
which both bind to the IL-1 type I receptor and elicit nearly four known chemokine subfamilies, differentiated according
similar effects. The primary sources of interleukin-1 are to the primary amino acid sequences: CXC, CC, C, and CX3C.
the myocardial cells themselves, although fibroblasts were The plasma concentration of chemokines increases signifi-
already shown to produce IL-1 too. Significantly increased cantly in heart failure, such as MCP-1α and RANTES (118).
production and release of IL-1 from fibroblasts were observed There are also neutrophil-specific chemokines, the CXC
in hypoxic states, like acute myocardial ischemia. IL-1 chemokines, including IL-8, neutrophil activating peptide-2
depresses myocardial function in a dose-dependent fashion, and GROα, whose elevated level is proportional to the sever-
synergistic with TNFα. Negative chronotrope and inotrope ity of the initiating disease. For instance, it has been proven
effects of IL-1 were found in animal experiments both in the in animal experiments that the overexpression of myocar-
whole heart and by isolated cells. Further, IL-1 is involved in dial CXCR4 results in enhanced recruitment of inflamma-
myocyte hypertrophy, apoptosis, and cardiac arrhythmogene- tory cells, increases TNFα production, and leads to acceler-
sis. Anakinra, a known recombinant human IL-1R antagonist, ated apoptosis and cell turnover. Furthermore, overexpressed
was shown to inhibit apoptosis in experimental murine acute CXCR4 in mesenchymal stem cells induced effectively
myocardial infarction model (1). neomyoangiogenesis in the infarcted myocardium (141).
Other proinflammatory mediators: C-reactive

Interleukin-6/IL-6 protein/CRP
IL-6 is a member of a cytokine family with homologous The pentameric C-reactive protein (CRP) is synthesized in
structure and overlapping biological effects. IL-6 signaling the liver and responds to acute inflammatory stimuli as an
requires the interaction of IL-6R and the membrane-bound acute phase protein. It binds specifically to microbial polysac-
gp 130, which makes cells susceptible to IL-6. The activa- charides, opsonizes ligands for phagocytosis, and induces
tion of the IL-6 receptor complex leads to various signaling the classical complement pathway via the C1Q complex
pathways, involving different transcription factors, such as (7). According to experimental investigations, an increased
STAT1 or STAT3 (49). The circulating levels of IL-6 and gp serum CRP level presents a deleterious factor in myocar-
130 are increased in congestive heart failure and also corre- dial infarction model: the i.v. injection of human CRP into
late with its progression and functional class. IL-6 and other rats after coronary artery ligation augmented infarct size by
IL-6 related cytokines can induce cardiomyocyte hypertro- approximately 40%, while complement depletion completely
phy in different cell signaling pathways, including STAT3 abolished this effect (47). Administration of a potent CRP
transcription factor. Based on experiments with cultured car- inhibitor, 1,6-bis-(phosphocholine)-hexane, to rats after acute
diomyocytes, IL-6 cannot act directly on cardiomyocytes; its myocardial infarction increases infarct size and cardiac dys-
effects depend on the availability of the soluble IL-6R recep- function, induced by human CRP (98). Clinical investiga-
tor within the myocardium. IL-6 plays also an important part tions also corroborated the hypothesis that CRP is a possi-
in the development of myocardial dysfunction and muscle ble predictor in cardiac dysfunction. The Framingham Heart
wasting, correlates with the decreased functional status of the Study revealed that patients with elevated CRP serum lev-
patient, and provides prognostic information (136). els (>5 mg/L) express a significantly increased risk of heart

failure. Moreover, the Rotterdam study was designed to inves- Neutrophils

tigate the relation between lower serum CRP concentrations
and clinical outcome of heart failure, and defined CRP as a Neutrophils have a paradox role in heart failure due to
promising, independently associated predictor (56). their dual and contrary functions in inflammatory processes.
Neutrophils principally destroy invading microorganisms by
secreting toxic chemicals, such as ROS or defensins. How-
ever, the mechanisms, with which neutrophils are able to kill
Cellular elements in heart failure microorganisms in inflammation, has also the potential to
Monocyte-macrophage system impair normal tissue structure. After acute injury of the heart,
neutrophils are recruited contributing to healing processes
Circulating inflammatory monocytes and macrophages are and scar formation in the myocardium. It has been shown
among the first leukocytes infiltrating the heart during the that intense neutrophil chemotactic activation and LTB4 gen-
early proinflammatory phase after myocardial infarction. eration presenting in unstable angina pectoris or myocardial
They participate in inflammatory and reparative processes, infarction relate to cellular activation in myocardial ischemia
and thereby determine left ventricle remodeling (74). Animal (84). Neutrophils are recruited in the infarcted myocardium
experiments showed that monocytes/macrophages dominate in the first hours after onset of ischemia and peak after one
in the cellular infiltration in the first two weeks after myocar- day.
dial 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 T-cell subsets
repair. Furthermore, it could be of therapeutical importance to Whereas most research focused on the infiltration of innate
modulate the timing and intensity of recruitment, or the ratio immune cells, it became recently clear that also adaptive
of subsets in tissue repair after MI. Macrophages are diverse immune cells are involved in the pathophysiology of heart
extravascular immune cells, distributed in the whole human failure. Activation of T-cells occurs mainly in lymph nodes
body and acting on several cell types. There are two differ- draining the heart. Especially regulatory T-cells seem to be
ent types of macrophages known, the inflammatory, classical, involved in healing after myocardial infarction by influencing
or M1 macrophages, and the reparative, alternative, or M2 the conversion from proinflammatory M1 to pro-healing M2
macrophages. The different types of macrophages, derived macrophage (132). In contrast, ablation of B cells improved
from circulating monocytes are crucially involved in inflam- healing after myocardial infarction (142).
matory tissue remodeling in heart failure. They possibly inter-
act with the surrounding extracellular matrix cells, cardiac
myocytes, and endothelial cells.
Biochemical Changes in Heart Failure
Cardiac contraction and relaxation abnormalities are gener-
Adhesion molecules ally attributed to deleterious changes in numerous cellular
Adhesion molecules are cell surface receptors, which ensure processes, for example, metabolic pathways, ion channels
the binding of leukocytes to each other, to the endothelium, or and pumps controlling excitation contraction coupling, and
to the extracellular matrix components. In heart failure, three contractile proteins. These alterations may present either the
different adhesion molecule groups have been defined: The primary cause for the impaired cardiac function, or may
immunoglobulin group, including the intracellular adhesion occur secondary due to pressure or volume overload. They
molecules (ICAM-1, -2, and -3) and the vascular cell adhesion altogether reduce myocardial contractility and slow down
molecules (VCAM-1) (9, 120). Integrin heterodimers, which relaxation. There are two known biochemical mechanisms
mediate lymphocyte adherence to the vascular endothelium, resulting in depressed cellular function in the myocardium:
especially LFA-1 and Gp IIb-IIIa in heart failure. Selectins are energy starvation, which acts by decelerating the biochemi-
single-chain transmembrane glycoproteins, involving three cal processes and inhibiting cellular interactions, and struc-
different subsets according to the specific binding object, tural/functional abnormalities in contractile proteins.
namely the E-selectins (endothelial), P-selectins (platelet),
and L-selectins (leukocytes), respectively. These molecules
support the adhesion of leukocytes to the endothelium and Excitation contraction coupling and relaxation
extravasation. It was suggested that elevated platelet surface Excitation contraction coupling is a physical term, which
P-selectin indicates increased thrombogenicity and is spe- describes the conversion of an electrical stimulus to a mechan-
cific for decompensated heart failure. However it has been ical response. In the myocardium it includes processes, which
shown that platelet abnormalities relate rather to the associ- connect the depolarization of the plasma membrane and the
ated comorbidities and occur in stable heart failure as well, cytosolic release of calcium. This cytosolic calcium tran-
despite of antiplatelet medication usage (29). sient activates calcium-sensitive, ATP-dependent contractile

Na+ K+
Na+/Ca2+
exchanger
×Na+
3×
Ca2+
Ryanodine
Sarcoplasmic
reticulum
Ca2+ Ca2+ ATPase
K+ Ca2+ Ca2+ -uptake

pump
Na+ Ca2+
Na+/K+
pump
L-type Ca2+ Ca2+ Troponin
channel complex
Sarcomere
Figure 5 Excitation-contraction coupling in physiological and pathological state.
myocardial proteins. With the cleavage of high-energy phos- Physiologically, cytosolic calcium concentration is reg-
phates, the shortening of these proteins causes synchronized ulated by beta-adrenoreceptor-coupled mechanisms. Beta-
global contraction of the heart (16). adrenergic stimulation increases cAMP, which induces pro-
An initiating cardiac action potential is generated by the tein kinase (to modulate L-type calcium channels to release
pacemaker cells of the heart and conducted to all cells in the calcium) or activates the IP3 signal transduction path-
heart via gap junctions. By activating membranous T tubules, way, which can stimulate the release of calcium by the
Ca2+ is forced to enter the cell matrix via sarcolemmal L- sarcoplasmic reticulum through IP3. Moreover, the beta-
type calcium channels and in the early phase possibly via adrenergic-dependent activation of the cAMP-dependent pro-
sodium-calcium exchanger. The increase in Ca2+ concentra- tein kinase phosphorylates phospholamban, a protein located
tion is detected by ryanodine receptors (RYRs) in the mem- on the sarcoplasmic reticulum that normally inhibits (72)
brane of the sarcoplasmic reticulum. RyRs represent a class calcium uptake. This disinhibition of phospholamban leads
of cellular calcium channels in various contractile tissues. to an increased rate of calcium uptake. Therefore, beta-
They are the major cellular mediators of the positive feedback adrenergic stimulation increases the contractility (positive
mechanism calcium-induced calcium release (CICR) in cells inotropy), and increases the rate of relaxation (positive
(36). These receptors are activated by a calcium trigger and lusitropy).
release calcium molecules from the sarcoplasmic reticulum. In heart failure excitation contraction coupling is impaired
The released calcium molecules bind to Troponin C, which in some way (45, 134). It can be impaired by decreased
moves to the actin-binding site of the tropomyosin complex transport of calcium into the cell through L-type calcium
and induces conformational change. ATP hydrolyses at this channels. Dysfunction or lower amount of the L-type calcium
place and myosin heads pull the actin filaments toward them- channels play a central role in it; decreased cardiac L-type
selves and thereby shorten the sarcomere length (see in Fig. 5). Ca2+ channel activity induces cardiac hypertrophy and heart
Relaxation is also an energy-dependent process, in which cal- failure in mice (46). The calcium sensitivity of Troponin C or
cium is actively transported back to the primary emerging the myofilaments can also be reduced. Thus, calcium increase
cell organelles (27). Calcium is mainly taken up by the sar- in the surrounding of the troponin complex significantly
coplasmic reticulum by an ATPase pump (SERCA, sarco- attenuates excitation contraction coupling. In some forms
endoplasmic reticulum calcium-ATPase) (99). At the end of of diastolic heart failure, the function of the sarcoplasmic
the cycle—after intracellular calcium concentration drops— ATP-dependent calcium pump is impaired. This defect delays
all participants in the excitation contraction coupling return the rate of calcium uptake by the sarcoplasmic reticulum and
into their steady state, a new ATP binds to the myosin head, reduces the rate of relaxation, leading to diastolic dysfunction
displacing ADP and the initial sarcomere length is restored. (86).

Metabolism in heart failure damage participates in the dysfunction of mitochondria as

well. The functional changes and structural abnormalities of
The heart needs and consumes more energy than any other
the mitochondria are also detectable in end-stage heart fail-
organ of the human body. To reach this enormous demand,
ure: the mitochondrial volume becomes decreased, and an
the heart converts chemical energy stored in fatty acids and
increased amount occurs in the failing heart.
glucose into mechanical energy. If these mechanisms do not
Thirdly, impaired ATP transfer and utilization may limit
reach the demand of the heart, cardiac malfunction, mechani-
contractile function. The phosphocreatine shuttle, which pro-
cal failure of the heart occurs (50, 55, 108, 114, 127, 139). The
vides ATP for the cells and retransports ADP, depends on
“energy starvation” hypothesis subsumes the altered mecha-
reactions catalyzed by creatine phosphokinase, an enzyme
nisms of myocardial energetics, which lead to energy deple-
that transfers high-energy phosphates to the cytosol and ADP
tion. The metabolic and energy production patterns in the
to phosphocreatine. The rate-limiting step in energy produc-
failing heart mimic the patterns in the fetal heart.
tion in the heart is the ADP-rephosphorylation and retrans-
Cardiac energetics is based on three main mechanisms,
port to the mitochondria. Creatine phosphokinase levels are
namely, the utilization of the components, energy produc-
decreased in heart failure, slow rephosphorylation of ADP,
tion and transfer of high-energy phosphates to the myofibers.
and thus play a major role in energy starvation in heart fail-
The sources include free fatty acids and glucose, processed
ure. Compensation by isoform switch from M (adult) to B
by beta-oxidation or glycolysis. The metabolic products than
(fetal) is possible, and provides another evidence of the sug-
enter the Krebs cycle and the mitochondrial respiratory chain.
gested switch to fetal metabolic pattern in heart failure. The
Here high-energy phosphate ATP is produced by oxidative
allosteric effects of ATP, such as accelerating ion pumps, facil-
phosphorylation. ATP is then transported to the myofibrils by
itating ion exchangers, and passive ion fluxes, are also signif-
the creatine-kinase energy shuttle. In heart failure changes
icantly reduced in heart failure. It affects even calcium fluxes,
occur in all three components of cardiac energy metabolism:
which mediate excitation contraction coupling. The lack of
substrate utilization, oxidative phosphorylation, and high-
ATP fails to accelerate the calcium flux into the sarcolemma
energy phosphate metabolism.
and sarcoplasmic reticulum, which leads to reduced contrac-
Substrate utilization can become limiting for cardiac func-
tility. Relaxation is also involved, as the low availability of
tion in heart failure which may occur as a result of reduced
ATP fails to stimulate the active transport of calcium out of
substrate uptake, oxidation, or as a change in the relative
the cytosol and Na+ /Ca2+ exchanger. As side-effect, sodium
contributions of fatty acids (60%-90%) and glucose (10%-
accumulates, and intracellular potassium decreases, which is
40%) to ATP synthesis. In early heart failure, most studies
arrhythmogenic, because low potassium levels lead to depo-
showed constant or slightly increased fatty acid utilization
larization of the plasma membrane. Reduced free energy by
and increased glucose utilization; however, in advanced heart
impaired terminal phosphate hydrolysis of ATP plays also a
failure, both of them decrease but with a constant ratio in car-
role in energy starvation. Thus there is a cardiac phosphoryla-
diac metabolism. In advanced heart failure, the activated sym-
tion reserve; a small decrease in the phosphorylation activity
pathetic system enhances insulin resistance, decreases insulin
can impair ATP-dependent reactions.
release from the pancreatic beta cells, increases hepatic glu-
cose production through gluconeogenesis and glycogenolysis,
and increases glucagon production. Enhanced sympathetic
activity and RAAS increase the serum level of free fatty acids Oxidative Stress in Heart Failure
by activated lipolysis and thereby inhibits the uptake of glu-
Several experimental and clinical studies suggest that oxida-
cose in the muscles, and damages the pancreas by cytokines
tive stress contributes to the development and progression of
such as TNFα. Therefore, plasma glucose rises and provokes
heart failure.
a pancreatic insulin response, which is not adequate to con-
trol hyperglycemia. Increased plasma levels of free fatty acids
and glucose also predispose to increased hepatic synthesis of Oxidative stress
triglycerides.
Activated oxidative stress state has been proved in human
Secondly, impaired energy production can reduce cardiac
heart failure: in patients with ischemic and nonischemic
function by providing an insufficient supply of ATP to cardiac
heart failure malondialdehyde-like activity, a marker of lipid
myocytes (125, 126). The most important factor that deterio-
peroxidation, is increased. There are several other mech-
rates high-energy phosphate production and availability is the
anisms and molecules, which have been demonstrated to
reduced oxygen supply of cardiomyocytes. Impaired coronary
play an important role in human heart failure, such as
blood flow leads to an imbalance between oxygen and energy
biopyrrins (oxidative metabolites of bilirubin), nitrotyrosins
demand and supply. The increasingly produced ROS damage
(intracellular marker of oxidative stress), or xanthine-oxidase
the mitochondrial DNA, and because of its poor repair capac-
activity. The exact mechanism of oxidative stress impair-
ity, fragmented mitochondrial DNA accumulates and leads to
ing cardiac function is not completely understood; however,
further impairment of the energy homeostasis (91). Besides
there are potential molecular processes, which take part in
the deleterious effects of free radicals, an antibody-mediated
it: the activation of proinflammatory mediators, repetitive

ROS
MAPK
JNK, p38, Akt
MMPs
RyR
NF-κβ DNA
AP-1 damage
PARP-1
activation
Nucleus Sarcoplasmic Mitochondrium
reticulum
Inflammation
Contractile
Apoptosis Fibrosis Apoptosis
dysfunction
Necrosis
Figure 6 Oxidative stress in heart failure.
ischemic and reperfusion periods, or auto-oxidation of cate- chemistry under pathological conditions (87). Moreover, at
cholamines. The activation of redox-sensitive signaling path- increased levels of oxidative stress, O2 − interacts with NO
ways (e.g. mitogen-activated protein kinases) and transcrip- and forms peroxynitrite. Peroxynitrite is potent reactive oxy-
tion factors (e.g. NF-κB) are implicated in the development of gen derivate, which triggers several cytotoxic processes such
cardiomyocyte hypertrophy (116). Decreased antioxidant as lipid-peroxidation or protein oxidation (38). The altered
activity is also suggested to promote oxidative stress. Addi- proteins influence the fine-tuned excitation-contraction cou-
tionally, the well-known risk factors for cardiovascular dis- pling and may activate ECM modulating systems like MMPs.
eases, like hypertension, diabetes, or obesity, are also associ- They can regulate fibroblast proliferation or collagen synthe-
ated with increased oxidative stress. One possible mechanism, sis, and are involved not only in MMP activation but also in
how oxidative stress and reactive metabolites impair cardiac increased MMP expression. Some potential sources of ROS
performance is through direct damage of cellular proteins and include proinflammatory cells, mitochondria, xanthine oxi-
membranes as well as cellular dysfunction and death. Another dase, and NADPH oxidases. Elevated mitochondrial-derived
mechanism is the potential of ROS to activate MMPs which ROS activation, or induced xanthine-oxidase expression and
leads to the reorganization of the extracellular matrix. Oxida- activity are potential sources of reactive species. Also in clin-
tive stress mechanisms in heart failure are shown in Figure 6. ical studies, patients treated with xanthine-oxidase inhibitor
allopurinol after myocardial infarction, had over time lower
plasma MMP activity and urinary 8-iso-prostaglandin F2-
Reactive oxygen species levels, than those in the control group (53). The NADPH
High ROS are produced by normal aerobic metabolism. ROS oxidases, a group of oxidizing enzymes, are also thought
include oxygen-containing free radicals, such as superoxide to contribute to ROS generation. Several pathophysiological
anion (O2 – ), hydroxyl radical, and compounds, such as hydro- stimuli involved in chronic heart failure, such as the activa-
gen peroxide (H2 O2 ). These reactive elements participate in tion of the neurohumoral system (involving angiotensin II, β-
both normal and pathologic biochemical reactions. Super- adrenergic agonists, endothelin-1, or tumor necrosis factor α)
oxide anion is generated intracellularly by the incomplete or myocyte stretch can stimulate ROS production by NADPH
reduction of O2 , by nicotinamide-adenine dinucleotide phos- oxidase induction. Under physiological conditions there is a
phate (NADPH) oxidase or xanthine oxidase (XO), uncou- precisely regulated balance between the production of ROS
pling of NO synthase (NOS), and electron transport and and the molecules, which are capable of “scavenging” ROS.
“leakage” during oxidative phosphorylation in the mitochon- Experimental animal studies suggest, that oxygen free radi-
dria. It can spontaneously or enzymatically lead to hydrogen- cals can exert direct toxicity on the myocardial structure and
peroxide (H2 O2 ) production. H2 O2 is able to generate the function. These effects can be reversed by free radical scav-
formation of the highly reactive hydroxyl radicals via Fenton engers. For instance, superoxide anion is a potent inhibitor of

nitric oxide, and the reduced bioavailability of NO contributes stress-induced, proapoptotic, proto-oncogene p66shc , which
to endothelial dysfunction. The Janus-faced NO is able to definitely links oxidative stress and apoptosis in an experi-
act against deteriorating oxidative processes by activating mental pacing-induced heart failure model (25).
several potent antioxidant enzymes, such as xanthine-oxidase
or NADPH oxidase. Further, ROS stimulate myocyte growth
and ECM remodeling. They activate transcription factors, Role of the mitochondria in heart failure
hypertrophy (Src and PI3K) and apoptosis (p38 and Akt) It is of great interest, if mitochondria, as an important source
signaling pathways. of ROS are active participants in the development of heart
ROS also play an important role in G-protein-coupled failure. They generate high-energy phosphates by several
hypertrophic stimulation by angiotensin II or β-adrenergic oxidation-reduction reactions, supported by enzymes form-
stimulation. Reactive species can effectively modulate other, ing respiratory complexes. The electron transfer in these res-
physiological signaling pathways (called “redox signaling”) piratory complexes is often followed by an electrochemical
as well, for example, the induction of the expression of gradient by proton transport from the mitochondrial matrix to
proteins involved in excitation-contraction coupling (such as the inner membrane. This electrochemical proton gradient—
ion channels, sarcoplasmic reticulum calcium release chan- or as often called, protonmotive force—provides the energy
nels) or myofilament proteins, protein kinases (113) (see table for the high-energy phosphate formation. If the oxidation-
12). Table 12. Reactive species may also play an important reduction processes are incomplete, superoxide and other
part in both adaptive and maladaptive processes (e.g., the early reactive oxygen-containing species will be generated. Low
development of hypertrophy and adverse remodeling respec- amount of ROS are built under physiological circumstances as
tively). Cesselli et al. have pointed out the link between the well, but the endogenous antioxidant enzymes, such as super-
induction and modifications in multiple pathways, involved oxide dismutase, manage to eliminate them. In heart failure,
in mediating oxidative metabolism and apoptosis, as well as the mitochondrial ROS production is augmented, leading to an
in the progression of left ventricular dysfunction. Further, excessive imbalance in the oxidative-antioxidative processes.
the author presents a new signaling molecule, the oxidant Mitochondria contribute to apoptotic processes as well, by
Table 12 Oxidative Modifications of Protein Kinases
PKA Rl subunit oxidation ↑ R1 binding to AKAPs (α-MHC) 32

↑ PKAI kinase activity
Catalytic domain Cys199 -S-glutathionylation ↓ Kinase activity 34-36
PKG 1α Oxidation of Cys42 in the homodimerization domain ↑ Affinity for substrates 38
↑ cGMP-independent catalytic activity
PKC Oxidation of C1 domain Cys residues ↓ Autoinhibition 59
↑ Kinase activity
Calpain-dependent cleavage, release of a constitutively ↑ PKCα catalytic activity 8.85-87
active catalytic domain fragment ↑ PKCδ-dependent phosphorylation of
14-3-3
Oxidation of a conserved activation loop Cys ↓ Kinase activity 36, 59
Src-dependent phosphorylation of PKCδ at Tyr311 Altered substrate specificity, acquisition of 40
cTnl-T144 kinase activity
PKD c-Abl- and Src-dependent phosphorylations of PKD at ↑ Kinase activity 50, 51
Tyr463 and Tyr95 that relieve autoinhibition, promote
PKCδ-dependent PKD phosphorylation at Ser744 /Ser743
CaMKII Met231 /Mel282 oxidation ↑ Ca2+ -independent catalytic activity 76
ASK-1 Mechanisms that disrupt a C-terminal interaction with ↑ Kinase activity 66-68
14-3-3: dephosphorylation of Ser967 at the ASK-1
C-terminus or phosphorylation of 14-3-3 by
ROS-regulated kinases (PKD. Mst1, catalytic fragment of
PKCδ). Mechanisms that disrupt an N-terminal interaction
with Trx-1 (Trx-1 oxidation)
Mst1 Caspase-dependent cleavage of an autoinhibitory ↑ Kinase activity 60
domain
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.

Table 13 Abbreviations
ACC: American College of Cardiology ICF: Impaired cerebral function

ACE: Angiotensin converting enzyme LV: Left ventricle
ADH: Antidiuretic hormone LVRR: Left ventricle reverse remodeling
ADH: Antidiuretic hormone MCI: Mild cognitive impairment
ADM: Adrenomedullin MCP-1α: Monocyte chemoattractant protein-1α
AHA: American Heart Association MI: Myocardial infarction
ANP: Atrial natriuretic peptide MMP: Matrix metalloproteinase
AT: Angiotensin NAP-2: Neutrophil activating peptide-2
ATP: Adenosine triphosphate NE: Norepinephrine
ATR: Angiotensin receptor NET: Neutrophil extracellular traps
AVP: Arginine vasopressin NO: Nitric oxide
BNP: Brain natriuretic peptide NOS: Nitric oxide synthase
CAD: Coronary artery disease NPR: Natriuretic peptide receptor
cAMP: Cyclic adenosine monophosphate NSTEMI: Non-ST-elevation myocardial infarct
CHF: Chronic heart failure NT-proBNP: N-terminal probrain-natriuretic peptide
CICR: Calcium-induced calcium release NYHA: New York Heart Association
CIF: Cotransport inhibitory factor PVA: Pressure-volume area
CIND: Cognitive impairment with no dementia PV-Loop: Pressure-volume loop
CO: Cardiac output RAAS: Renin angiotensin aldosterone system
COPD: Chronic obstructive pulmonary disease RANTES: Regulated on activation normal T cell expressed
and secreted
Ea: Arterial elastance
RED-HF: Reduction of events by darbepoetin alfa in heart
ECM: Extracellular matrix failure
EDRF: Endothelium-derived relaxing factor RWT: relative wall thickness
EF: Ejection fraction RyR: Ryanodine receptor
ESC: European Society of Cardiology SERCA: Sarco-endoplasmic reticulum calcium ATPase
EDPRV: End-diastolic pressure-volume relationship STAMINA-HeFT: Study of Anemia in Heart Failure Trial
ESPRV: End-systolic pressure-volume relationship STEMI: ST-elevation myocardial infarct
ET: Endothelin SV: Stroke volume
GDF-15: Growth-differentiation factor-15 SW: Stroke work
GPCR: G-protein-coupled receptors TACE: TNFα converting enzyme
GRK: GPCR receptor kinase TIMP: Tissue inhibitor of metalloproteinase
GTP: Guanosine triphosphate TNFR: TNFα receptor
HDAC: Histone deacetylase XO: Xanthine oxidase
HF-PEF: Heart failure with preserved ejection fraction UTR: Urotensin receptor
HF-REF: Heart failure with reduced ejection fraction
releasing cytochrome c, which represents an initiating sig- Antioxidant systems

nal for the apoptosis mediator caspase family. The fact, that
The role of the endogenous antioxidant systems is to coun-
mitochondrial high-energy phosphate formation is the major
terweigh the deleterious effects of ROS: the enzymatic and
source for energy supply for cardiomyocytes, suggests that
nonenzymatic antioxidants are the executor of the scavenge
pathological changes in mitochondrial energy metabolism are
mechanisms of ROS. The intrinsic antioxidant effectors
strongly related to myocyte dysfunction, apoptosis, and devel-
include enzymes such as catalase, glutathione peroxidase,
opment of heart failure (90, 92).
superoxide dismutase, or nonenzymatic antioxidants like

vitamin C, E (96), N-acetylcystein (137, or ubiquinone. These may occur, presenting as a cardiogenic dementia or heart
effectors convert ROS into harmless molecules, which are failure-induced depression.
neutral in terms of apoptosis or oxidative damages. A further Great effort has been made to reverse the progressing
antioxidant system is represented by the thioredoxin system remodeling processes to maintain a stable state. Beside novel,
(70), including thioredoxin, thioredoxin-reductase, and optimized pharmacotherapeutical regimes, interventional and
NADPH, which acts as a protein-disulfide oxidoreductase. surgical methods have also made a remarkable progression
NO is a further well-known vasoactive and reactive molecule, during the past decades. Reverse remodeling was success-
which stimulates the formation of cGMP. Its target molecule, fully reached by many procedures, for instance, significant
cGK-1 (protein kinase G1) modulates myocyte function and improvement could be detected after cardiac resynchroniza-
growth, and regulates remodeling. tion 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
Conclusions of its clinical importance for the design of novel therapeutical
approaches.
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
Acknowledgements
combination of reduced CO and increased afterload. Both of The authors wish to thank the following colleagues for
these concepts describe cardinal features of heart failure, but their participation in the writing of this chapter: Dr. G.
neither of them explains its constant progression. Therefore, Ramos, Dr. J. Weirather, and Dr. B. Vogel. This work was
a novel progressive model of heart failure was established. supported by grants from the Bundesministerium für Bil-
The development of heart failure follows a primary cardiac dung und Forschung (BMBF01 EO1004) (S. Frantz) and by
event. It can occur acutely such as in myocardial infarction, the Deutsche Forschungsgemeinschaft, SFB688 TP A10 (S.
or chronically such as in cardiomyopathies. Frantz).
Independently of the underlying cause, conserved macro-
and microstructural, cellular, and molecular processes are set
into motion, following the same pathway and resulting in
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JWBT335-c140055 JWBT335-CompPhys-3G-v1 Printer: Yet to Come November 25, 2015 10:11 8in×10.

Pathophysiology of Heart Failure

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Comprehensive Physiology Pathophysiology of Heart Failure

Etiology and Risk Factors Pregnancy (physiologic)

r CAD, myocardial ischemia, and myocardial infarction

r Hyperglycemia, impaired glucose tolerance, and diabetes

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r Hypercholesteremia EF is normal (called heart failure with preserved ejection

190 Volume 6, January 2016

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Comprehensive Physiology Pathophysiology of Heart Failure

Figure 1 PV loop showing the correlation of pressure and volume alterations in

dP/dtmin and dP/dtmax : These parameters define the minimum

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subsumes alterations in heart dimensions, mass, and shape Reverse remodeling

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Normal Physiological state Physiological myocardial mass, diameter,

Concentric Arterial hypertension Increased wall thickness

Eccentric Mitral valve regurge Increased mass

Combined Myocardial infarction Dilation in nonfunctioning areas

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P13K PLA2 Src CREB Troponin I RyR CaMKII

Apoptosis Inotropy Hypertrophy Lusitropy Inotropy Apoptosis

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

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Angiotensin 1-7 Angiotensin II

Heart Kidney Other effects

Figure 4 Major effects and further metabolization of angiotensin II.

ADH/antidiuretic hormone/arginine vasopressin overload by activated V2 receptors contribute to ventricular

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AT1R AT2R Elevated plasma Low plasma natriuretic

Heart (nerves) Heart (ﬁbroblasts, Hypertensive heart Mitral stenosis

Liver Fetal, neonatal tissues Hyperthyreosis Left cardiac tumors

Lung Cardiac amyloidosis Constrictive

Increased vasopressin Increased NO release Atrial tachyarrhythmia

targets involve pro- and anti-inflammatory cytokines, endo-

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Other proinﬂammatory mediators: C-reactive

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