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Pathophysiology of heart failure with reduced ejection

fraction: Hemodynamic alterations and remodeling
Authors: Wilson S Colucci, MD, Jay N Cohn, MD
Section Editor: Stephen S Gottlieb, MD
Deputy Editor: Susan B Yeon, MD, JD, FACC

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2020. | This topic last updated: Jul 06, 2020.

INTRODUCTION

Heart failure (HF) is a clinical syndrome caused by impairment of ventricular filling or ejection of
blood [1], which results in the inability of the heart to provide adequate perfusion to the tissues
while maintaining normal cardiac filling pressures. HF is associated with a variety of interrelated
structural, functional, and neurohumoral alterations with beneficial as well as maladaptive
effects.

This topic will discuss the hemodynamic and remodeling aspects of the pathophysiology of HF,
particularly HF with reduced ejection fraction (HFrEF; left ventricular ejection fraction [LVEF]≤40
percent) and HF with mid-range ejection fraction (HFmrEF; LVEF 41 to 49 percent). The
pathophysiology of neurohormonal alternations in HF, the diagnosis and management of HFrEF
and HFmrEF, and the pathogenesis of HF with preserved ejection fraction (HFpEF, LVEF ≥50
percent) are discussed separately. (See "Pathophysiology of heart failure: Neurohumoral
adaptations" and "Evaluation of the patient with suspected heart failure" and "Determining the
etiology and severity of heart failure or cardiomyopathy" and "Treatment and prognosis of
heart failure with mid-range ejection fraction" and "Pathophysiology of heart failure with
preserved ejection fraction" and "Overview of the management of heart failure with reduced
ejection fraction in adults".)

LVEF CATEGORIES AND LIMITATIONS

As discussed below, the two major types of ventricular dysfunction that lead to HF are systolic
dysfunction (impaired cardiac contractile function) and diastolic dysfunction (impaired cardiac
filling), although these mechanisms are often concurrent (see 'Pressure-volume relationships in
HF' below). For clinical purposes, HF due to left ventricular (LV) dysfunction is categorized
according to LV ejection fraction (LVEF). Nearly one-half of patients with HF have HFrEF (LVEF
≤40 percent), and nearly one-half have HFpEF (LVEF ≥50 percent) [2]. The remaining 10 to 24
percent of patients with HF have HFmrEF (LVEF 41 to 49 percent) [3-14].

However, categorization of LV function and HF by LVEF is not based upon etiology or

pathophysiology, but rather by clinical convention given the prognostic value of LVEF, inclusion
of LVEF thresholds as criteria in clinical HF trials, and the widespread availability of methods to
measure LVEF (particularly echocardiography). LVEF is not a robust measure of contractility [15],
commonly changes over time, and is subject to substantial variability among and within
modalities. (See 'Contractility' below and "Tests to evaluate left ventricular systolic function",
section on 'Left ventricular ejection fraction'.)

Patients with the same LVEF may have differing underlying pathophysiology and prognosis.
Despite these limitations, depressed LVEF is an adverse prognostic indicator in HF patients, with
increasing morbidity and mortality as LVEF falls below 40 to 50 percent. (See "Predictors of
survival in heart failure with reduced ejection fraction", section on 'Left ventricular ejection
fraction' and "Prognosis of heart failure", section on 'Factors affecting mortality rates'.)

NORMAL LV PRESSURE-VOLUME RELATIONSHIP

As a pump, the ventricle generates pressure and displaces a volume of blood. The three major
determinants of LV performance (reflected as stroke volume) are the preload (reflected by
venous return and end-diastolic volume), myocardial contractility (the force generated at any
given end-diastolic volume), and the afterload (aortic impedance and wall stress) [16]. The
relationship between LV pressure generation and ejection can be expressed as a plot of LV
pressure versus LV volume ( figure 1).

Preload — Preload is defined as the particular stretch or length of LV myocardial fibers at end-

diastole, which is determined by the resting force, myocardial compliance, and the degree of
filling from the left atrium. Landmark studies by Frank and Starling established the relationship
between ventricular end-diastolic volume (which is a measure of preload) and ventricular
performance (stroke volume). Increasing sarcomere length up to a point increases the degree
of overlap between actin and myosin filaments for force-generating cross-bridges, thereby
enabling increased tension development ( figure 2) [17]. Thus, there is an augmentation of
developed force as end-diastolic volume and fiber length increase up to a point. The LV
normally functions on the ascending limb of this force-length relationship.

Contractility — Myocardial contractility is defined by the force generated at any given preload.

Thus, the stroke volume at any given fiber length is a function of contractility, as variations in
contractility create nonparallel shifts in the developed force-length relation. The tension in each
myocardial cell is a function of the amount of calcium bound to a regulatory site on the
troponin complex of the myofilaments. The amount of calcium available is in turn a function of
intracellular calcium delivery.

Although LVEF is often assumed to be a measure of cardiac function, it is important to

recognize the profound effect of structural changes. LV remodeling results in myocyte
lengthening that increases chamber volume and results in an obligatory reduction in LVEF not
necessarily caused by impaired contractile function. (See 'Remodeling' below.)

Afterload — A third element determining ventricular performance is the afterload, the

impedance during ejection. The afterload on the shortening fibers is defined as the force per
unit area acting in the direction in which these fibers are arranged in the ventricular wall. This
constitutes the wall stress and can be estimated by applying Laplace's Law [18]. Changes in
ventricular volume and wall thickness, as well as aortic pressure or aortic impedance,
determine the afterload. As an example, elevations in systolic pressure reduce the ventricular
stroke volume at any given diastolic volume. In the normal heart, stroke volume is only
minimally altered by changes in afterload.

The relationship among preload, afterload, and contractility provides a type of feedback control
of myocardial function. A primary increment in stroke volume, for example, leads to an increase
in aortic impedance. As a result of this rise in afterload, subsequent contractions have an
attenuated stroke volume. If, on the other hand, an increment in aortic impedance is the initial
event, the accompanying reduction in stroke volume should lead to a greater end-ejection and
end-diastolic chamber volume. The ensuing prolongation of fiber length should restore stroke
volume to the baseline level.

PRESSURE-VOLUME RELATIONSHIPS IN HF

The two major types of ventricular dysfunction that lead to HF are systolic dysfunction
(impaired cardiac contractile function) and diastolic dysfunction (impaired cardiac filling),
although these mechanisms are interrelated and often concurrent. Systolic and diastolic
dysfunction of the LV can be understood by analysis of the relationships between LV-developed
pressure and volume [19-21].
LV systolic dysfunction refers to a decrease in myocardial contractility defined as an alteration in
the relationship between preload (often defined by LV filling pressure) and stroke volume. This
relationship is depicted by Frank-Starling curves, which identify a shift downward and to the
right as systolic dysfunction ( figure 3). As a result, the slope of the relationship between
initial length and developed force is reduced. This change is associated with a reduction in
stroke volume and, consequently, cardiac output.

Drug therapy can alter the developed force-length relationship. For example, the administration
of norepinephrine stimulates cardiac adrenergic receptors, which increase myocardial cell cyclic
adenosine monophosphate levels, thereby raising the intracellular calcium concentration and
contractility. As a result, the ventricle is able to develop a greater force from any given fiber
length. Administration of a beta blocker, on the other hand, attenuates the slope of the force-
length relationship.

Hemodynamic changes associated with systolic dysfunction trigger neurohumoral activation as

well as cardiac remodeling. The fall in cardiac output leads to increased sympathetic activity,
which helps to restore cardiac output by increasing both contractility and heart rate. The fall in
cardiac output also promotes renal salt and water retention, leading to expansion of the blood
volume, thereby raising end-diastolic pressure and volume, which, via the Frank-Starling
relationship, enhance ventricular performance and tend to restore the stroke volume (
figure 3). LV hypertrophy is also part of the adaptive response to systolic dysfunction, since it
unloads individual muscle fibers and thereby decreases wall stress and afterload. (See
'Remodeling' below and "Pathophysiology of heart failure: Neurohumoral adaptations".)

As systolic HF progresses, the progressive decline in the maximal cardiac output generated for
any given cardiac filling pressure can be represented as a series of Frank-Starling curves (
figure 3). Flattening of the Frank-Starling curve in advanced disease means that
augmentation in venous return and LV end-diastolic pressure (LVEDP) now fails to increase
stroke volume. The plateau in the Frank-Starling curve represents a reduction in the heart's
systolic reserve. As a result, the ability of positive inotropic agents to shift this relationship to
the left and permit greater shortening becomes impaired. In terms of the pressure-volume plot,
the systolic pressure-volume loop is "right-shifted," with a reduced slope representing the
decreased contractility. In contrast, the diastolic pressure-volume curve is initially normal,
although the pressure-volume loop for the patient with systolic dysfunction is shifted to the
right on the curve because of the increase in LV volume produced by cardiac dilation (
figure 4).

Two factors may contribute to a plateau in the pressure-volume curve:

 ● The heart may simply have reached its maximum capacity to increase contractility in
response to increasing stretch. In vitro studies suggest that this abnormality may result
from decreased calcium affinity for troponin C, and from decreased calcium availability
within the myocardial cells [22]. These abnormalities may result in part from lengthening of
the sarcomeres to a point that exceeds the optimal degree of overlap of thick and thin
myofilaments, thereby preventing developed force from increasing in response to
increasing load.

● The Frank-Starling relationship actually applies to LV end-diastolic volume, since it is the

stretching of cardiac muscle that is responsible for the enhanced contractility. The more
easily measured LVEDP is used clinically, since in relatively normal hearts, pressure and
volume vary in parallel. However, cardiac compliance may be reduced with heart disease.
As a result, a small increase in volume may produce a large elevation in LVEDP, but no
substantial stretching of the cardiac muscle and therefore little change in cardiac output
[23].

Decreased compliance due to hypertrophy and fibrosis may eventually produce disturbed
diastolic function in many patients with advanced HF [21]. In this setting, there is also an
upward shift in the end-diastolic pressure-volume relationship, as a higher pressure is required
to achieve the same volume.

The failing heart is progressively more afterload-dependent, and small changes in afterload can
produce large changes in stroke volume ( figure 5). Reducing afterload in patients with HF via
the administration of angiotensin converting enzyme inhibitors, angiotensin receptor blockers,
or direct vasodilators (eg, hydralazine) has the dual advantage of increasing cardiac output and,
over the long term, slowing the rate of loss of myocardial function. (See "Overview of the
management of heart failure with reduced ejection fraction in adults".)

REMODELING

Remodeling is defined as alteration in the structure (ie, dimensions, mass, and shape) of the
heart (also called cardiac or ventricular remodeling) in response to hemodynamic load and/or
cardiac injury, in association with neurohormonal activation and other factors. The process of
cardiac remodeling includes structural, functional, cellular, and molecular changes involving
cardiac myocytes and the interstitial collagen matrix.

Remodeling may be categorized as physiologic (adaptive) or pathologic (maladaptive) [24,25]:

 ● Physiologic remodeling is a compensatory change in the dimensions and function of the
heart in response to physiologic stimuli, such as exercise and pregnancy. This type of
remodeling is seen in athletes and has been called "athlete's heart." (See "Definition and
classification of the cardiomyopathies", section on 'Athlete's heart'.)

● Pathologic remodeling may occur with pressure overload (eg, aortic stenosis,
hypertension), volume overload (eg, valvular regurgitation), or following cardiac injury (eg,
myocardial infarction [MI], myocarditis, or idiopathic dilated cardiomyopathy). In each of
these settings, remodeling may transition from an apparently compensatory process to a
maladaptive one [26]. (See 'Adaptive versus maladaptive processes' below.)

Structural and functional changes — The remodeling process generally includes increases in

myocardial mass, and the myocyte is the major cell involved in the remodeling process. Other
components include the interstitium, fibroblasts, collagen, and coronary vasculature.
Myocardial hypertrophy is most properly defined as increased cardiomyocyte size with or
without an increase in overall myocardial mass; however, the term "hypertrophy" is used
clinically to denote increased myocardial mass and/or wall thickness.

Three general morphologic patterns of remodeling have been described ( figure 6) [26,27]:

● Pressure overload leads to concentric LV remodeling with or without an overall increase in

myocardial mass [28]. Concentric remodeling is characterized by increased relative wall
thickness (ventricular wall thickness as compared with cavity size). With concentric
hypertrophy, sarcomeres are added in parallel, and individual cardiomyocytes grow thicker.

● Volume overload or isotonic exercise leads to eccentric LV hypertrophy [28]. Eccentric LV

hypertrophy is characterized by increased cardiac mass and chamber volume. Relative wall
thickness may be normal, increased, or decreased. With eccentric hypertrophy, sarcomeres
are added in series, and individual cardiomyocytes grow longer.

● Following an MI, stretched, infarcted tissue increases LV volume, leading to combined

volume and pressure load on noninfarcted zones and mixed concentric/eccentric
hypertrophy. LV remodeling typically begins within the first few hours after the infarct, and
progresses over time [29-32]. The initial remodeling phase after an MI results in repair of
the necrotic area and scar formation that may, to some extent, be considered beneficial,
since there is an improvement in or maintenance of LV function and cardiac output [33,34].
The entire heart may be involved, as disproportionate thinning and dilation in the infarct
region (ie, infarct expansion) are accompanied by a distortion in shape of the entire heart
with volume-overload hypertrophy of noninfarcted myocardium [30,35]. As the heart
undergoes remodeling, it becomes less elliptical and more spherical ( figure 7) [36,37].
 There are also changes in ventricular mass, composition, and volume, all of which may
adversely affect cardiac function [35,38-41]. This cellular rearrangement of the ventricular
wall is associated with a significant increase in LV volume. Some studies have shown that
this volume increase is not a prerequisite to maintaining LV function.

Progressive remodeling is common after an initial, moderately large anterior wall Q-wave
infarction, but is unusual after an initial small inferior wall infarction [39]. Patients with no
or limited dilation at four weeks tend to remain stable, while those with progressive dilation
over this period tend to deteriorate over time with loss of function in initially normally
contracting myocardium (ie, pathologic remodeling) [35,38,39]. These changes are
important predictors of mortality [42]. However, mechanisms other than remodeling can
influence the course of heart disease, and disease progression can occur in the absence of
remodeling.

The importance of remodeling as an independent risk factor has been difficult to ascertain,
since factors leading to remodeling as well as the remodeling itself may be major determinants
of HF prognosis. Consistent with the hypothesis that remodeling is pathogenically important in
HF is the observation that angiotensin converting enzyme (ACE) inhibitors and some beta
blockers, which improve survival in patients with HF, can slow and in some cases even reverse
certain parameters of cardiac remodeling [43-47]. In addition, reversal of remodeling with
mechanical circulatory support in combination with medical therapy is associated with
improvement in LV systolic function in patients with advanced HF [48-51]. (See "Intermediate-
and long-term mechanical circulatory support" and "Overview of the management of heart
failure with reduced ejection fraction in adults".)

Adaptive versus maladaptive processes — As noted above, cardiac remodeling is both an

adaptive and a maladaptive process. The adaptive component enables the heart to maintain
function in response to pressure or volume overload in the acute phase of cardiac injury [52].

By comparison, progressive remodeling is deleterious and associated with a poor prognosis

[38,42]. There are no data to indicate when the transition from possible adaptive to maladaptive
remodeling occurs, or how this might be identified in patients. The occurrence of such a
transition and its time course may be expected to vary greatly. However, once established
beyond a certain phase, it is likely that remodeling actually contributes to HF progression. In
addition, it has been suggested that remodeling and the myocardial changes that accompany it
contribute to the pathogenesis of ventricular arrhythmias. (See "Ventricular arrhythmias during
acute myocardial infarction: Incidence, mechanisms, and clinical features".)
Cellular and molecular changes — Remodeling is associated with a number of cellular
changes that underlie structural remodeling, including myocyte hypertrophy, loss of myocytes
due to apoptosis [53-55] or necrosis [56], and fibroblast proliferation [57] and fibrosis [58,59].

Although the pathways and cells involved in LV remodeling are incompletely understood,
mechanisms at the molecular level have been proposed with neurohormonal activation
stimulating expression of proteins and myocyte hypertrophy [33,60-62]. (See 'Neurohormonal
activation' below.)

Cardiac myocytes — Myocytes and other cardiac cell types are thought to be fundamentally
involved in the remodeling process. After an insult of sufficient magnitude, myocyte numbers
decrease and surviving myocytes become elongated or hypertrophied as part of a
compensatory process to maintain stroke volume [40,41]; the thickness of the ventricular wall
also may increase due to myocyte hypertrophy [35,40,41].

Altered loading conditions (eg, increased preload) stretch cell membranes and increase wall
stress, which may play a role in inducing the expression of hypertrophy-associated genes. In
cardiac myocytes, this may lead to the synthesis of new contractile proteins and the assembly of
new sarcomeres. It is thought that the pattern in which these proteins are laid down
determines whether the cardiac myocytes elongate or increase their diameter [63]. The
increase in wall stress [40,61] may precipitate energy imbalance and ischemia, leading to a
vicious cycle of increased wall stress and wall thickness, with further energy imbalance and
ischemia.

Collagen synthesis and degradation — The myocardium consists of myocytes tethered and

supported by a connective tissue network composed largely of fibrillar collagen. Collagen is
synthesized by interstitial fibroblasts and degraded by locally produced enzymes called
collagenases, such as matrix metalloproteinases (MMPs). The significance of collagen synthesis
and degradation in cardiac remodeling and HF is supported by a variety of observations in
humans and in animal models [58,59,64-72].

Apoptosis — It has been proposed that increased apoptosis with loss of myocytes
contributes to progressive LV dysfunction in chronic HF [53]. The importance of this type of cell
death in human cardiac remodeling is not firmly established. However, in myocardial samples
from patients who underwent heart transplantation, apoptosis was increased more than 200-
fold in the failing heart [55].

Likewise, increased apoptosis is associated with the maladaptive response to sustained

pressure overload (increased afterload) in the rat [54]. Furthermore, in a mouse model of HF,
specific inhibition of apoptosis was beneficial [73]. Additional evidence that apoptosis is
involved in adverse remodeling and HF post-MI comes from mice in which the proapoptotic
protein Bnip3 was ablated [74,75].

Functional remodeling — While cardiac remodeling is primarily described on a structural

basis, "remodeling" may also occur at the molecular level, leading to alterations in the
expression and function of proteins that have important nonstructural effects on properties
such as contraction/relaxation, electrical activation, and metabolism. These molecular changes
are commonly associated with structural remodeling but, not infrequently, occur in the absence
of structural changes and, in either case, may have important consequences leading to
alterations in substrate utilization, the genesis of arrhythmias, and abnormalities in contraction
and relaxation.

Factors influencing cardiac remodeling — There are a number of factors that can influence
remodeling, including LV hemodynamics, blood pressure, and neurohormonal activation. The
time course and extent of remodeling are influenced by a variety of factors, including the
severity of the underlying disease, secondary events (such as recurrent ischemia), and
treatment [30,39,76]. Following an MI, the magnitude of remodeling changes is roughly related
to infarct size [39,40].

Alterations in hemodynamic load — Alterations in hemodynamic load caused by

myocardial injury influence the remodeling process. Early LV dilation in patients with anterior
wall infarction may be progressive. On the other hand, compensatory ventricular hypertrophy
appears to be a delayed and limited adaptation during the first year [39]. The net effect of
progressive ventricular dilation with insufficient reactive ventricular hypertrophy is a
considerable increase in global LV wall tension [39,77]. A number of mechanisms may be
stimulated by increased wall stress which, in the absence of effective therapy, may lead to
further dilation of the heart and progressive HF [41,78].

Blood pressure — Elevated blood pressure induces structural changes in the LV (eg,

hypertrophy, interstitial changes), which may result in diastolic dysfunction that may progress
to HF. The functional impact of pressure overload hypertrophy may be dependent on the nature
of the remodeling process. When remodeling is eccentric (LV enlargement with normal relative
wall thickness, but increased wall stress), a functional impairment leading to HF was observed
[79]. In contrast, HF did not occur in animals with concentric remodeling (normal chamber size,
increased relative wall thickness, and normal wall stress). There was no difference between the
two groups in myocardial mass or contractile function. (See "Clinical implications and treatment
of left ventricular hypertrophy in hypertension".)
 Neurohormonal activation — Progressive HF is associated with neurohumoral activation
that may be viewed initially as compensatory, but may be deleterious over the long term, in
part by contributing to pathologic remodeling [80]. Types and effects of neurohormonal
activation are discussed below. (See "Pathophysiology of heart failure: Neurohumoral
adaptations", section on 'Neurohumoral adaptations'.)

The data are most compelling for activation of the renin-angiotensin-aldosterone system.
Randomized trials have demonstrated that ACE inhibitors improve survival in HFrEF and can
slow (and in some cases even reverse) certain parameters of cardiac remodeling. These findings
indicate the importance of angiotensin II in pathologic remodeling [43-45]. Both systemic and
locally generated angiotensin II may participate in this process. (See "Initial pharmacologic
therapy of heart failure with reduced ejection fraction in adults", section on 'ACE inhibitor'.)

Aldosterone, the secretion of which is enhanced by angiotensin II, also may participate in
remodeling. The heart contains mineralocorticoid receptors and extracts aldosterone after an
MI, contributing to post-infarction remodeling [81]. In addition, the secondary
hyperaldosteronism commonly seen in HF may contribute to cardiac hypertrophy and fibrosis
[82,83]. Part of the survival benefit associated with spironolactone or eplerenone, which
compete for the mineralocorticoid receptor, may come from reduced fibrosis [84]. (See
"Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action",
section on 'Mineralocorticoid receptor antagonists'.)

Other factors — Other factors can also contribute to remodeling, including cytokines (tumor
necrosis factor-alpha [TNFa] and interleukins [IL]) [85], oxidative stress, MMPs, peripheral
monocytosis [86], and endothelin. (See "Pathophysiology of heart failure: Neurohumoral
adaptations", section on 'Endothelin'.)

● HF is often associated with increases in circulating proinflammatory cytokines (eg, TNFa, IL-
6, IL-1-beta and IL-2, and their soluble receptor or receptor antagonists) that become more
pronounced as myocardial function deteriorates [87-92]. Since inflammatory cytokines can
exert deleterious effects on the heart, it is possible that they play a role in the
pathophysiology of HF. Increased levels of proinflammatory cytokines and other
inflammatory markers may identify patients at increased risk of developing HF in the future
[93,94], and circulating concentrations of TNFa are increased in patients with HF in
proportion to the severity of the disease [87,95]. Conversely, infusion of pathophysiologic
concentrations of TNFa can produce changes similar to those seen in remodeling [96].
However, the clinical significance remains uncertain, as the use of inflammatory cytokine
antagonists has not been beneficial in patients with HFrEF [94,97].
 ● Oxidative stress refers to an imbalance between production of oxygen free radicals and
antioxidant defenses. There is increasing literature on its potential importance in
progressive HF. Although antioxidant therapies have not been shown to be of value in
patients with HF, markers of oxidative stress may be elevated in patients with HF. For
example, myeloperoxidase (MPO) is a leukocyte-derived enzyme that can produce a
cascade of reactive oxidative species, which may lead to lipid peroxidation, scavenging of
nitric oxide, and nitric oxide synthase inhibition [98,99]. Plasma MPO levels are elevated in
patients with chronic HFrEF [100], and elevated plasma MPO has been associated with an
increased likelihood of more advanced HF, and may be predictive of a higher rate of
adverse clinical outcomes [101].

● MMPs contribute to tissue remodeling in a number of disease states, such as an abdominal

aortic aneurysm (see "Clinical features and diagnosis of abdominal aortic aneurysm").
MMPs have also been implicated in cardiac remodeling [102,103], and in animal models,
remodeling can be attenuated by MMP inhibition [71,72,104].

● Peripheral monocytosis, which occurs two to three days after an acute MI, reflects
monocyte and macrophage infiltration of the necrotic myocardium. A higher peak
monocyte level is associated with a larger LV end-diastolic volume and lower LVEF. A peak
monocyte count ≥900/microL independently predicts HF, LV aneurysm formation, and
cardiac events [86].

SUMMARY

● Heart failure (HF) is associated with a variety of interrelated structural, functional, and
neurohumoral alterations with beneficial as well as maladaptive effects. (See 'Introduction'
above.)

● The three major determinants of the left ventricular (LV) performance (reflected as stroke
volume) are the preload (venous return and end-diastolic volume), myocardial contractility
(the force generated at any given end-diastolic volume), and the afterload (aortic
impedance and wall stress). (See 'Normal LV pressure-volume relationship' above.)

● The relationship between LV pressure generation and ejection can be expressed as a plot of
LV pressure versus LV volume (Frank-Starling curve) ( figure 1). (See 'Normal LV pressure-
volume relationship' above.)

● LV systolic dysfunction refers to a decrease in myocardial contractility; this is depicted as

reduction in the slope of the relationship between myocardial fiber length and developed
 force, and a shift to the right of the Frank-Starling curve ( figure 3). With LV diastolic
dysfunction, there is also an upward–shift in the end-diastolic pressure-volume
relationship, as a higher pressure is required to achieve the same volume. (See 'Pressure-
volume relationships in HF' above.)

● Remodeling is defined as an alteration in the structure of the heart in response to

hemodynamic load and/or neurohormonal activation. Pathologic remodeling may occur
with pressure overload (eg, aortic stenosis, hypertension), volume overload (eg, valvular
regurgitation), or following cardiac injury (eg, myocardial infarction [MI]). In each of these
settings, remodeling may transition from an apparently compensatory process to a
maladaptive one. (See 'Remodeling' above and 'Adaptive versus maladaptive processes'
above.)

• The three general patterns of remodeling are concentric LV remodeling (in response to
pressure overload), eccentric LV hypertrophy (in response to volume overload), or
mixed concentric/eccentric hypertrophy as may occur following MI ( figure 6). (See
'Structural and functional changes' above.)

• Structural remodeling is often associated with molecular events leading to changes in

the expression and/or activity of proteins involved in virtually every aspect of
myocardial function, including the hemodynamic, energetic, and electrical properties
of the heart.

• Factors influencing remodeling include alterations in hemodynamic load in response to

myocardial injury, blood pressure, and neurohormonal activation. (See 'Factors
influencing cardiac remodeling' above.)

● The hypothesis that remodeling is pathogenically important in HF is supported by the

observation that certain therapies (eg, angiotensin converting enzyme inhibitors) that
improve survival in patients with HF can slow or reverse certain parameters of cardiac
remodeling. (See 'Structural and functional changes' above.)

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Topic 3506 Version 17.0

GRAPHICS

Left ventricular pressure versus volume relationship

The normally contracting left ventricle ejects blood under pressure and the
relationship between left ventricular pressure generation and ejection can be
expressed in a plot of developed pressure versus volume. In the idealized pressure-
volume loop, the left ventricular end-diastolic pressure is represented by point A.
Isovolumic contraction at the beginning of systole is represented by line AB. As the
developed left ventricular pressure exceeds that of the aorta, the aortic valve opens at
point B. This leads to left ventricular ejection of blood (line BC). The volume of blood
ejected (point B minus point C) represents the forward effective stroke volume of this
contraction. At end-ejection, the aortic valve closes at point C followed by isovolumic
relaxation (line CD). The mitral valve then opens at point D with left ventricular
diastolic filling represented by line DA. The shaded area enclosed by the PV loop
(ABCD) represents the external left ventricular stroke work, which can be represented
mathematically as ∫PdV.

LV: left ventricle.

Graphic 73169 Version 2.0

Relationship between myocardial sarcomere length and tension

Top panel (A) is a schematic of a sarcomere. The thin filaments (actin, shown in black) are attached at the Z
band. The length of two actin filaments as they extend from the Z band is indicated by "b." The length of a
thick filament (myosin, shown in maroon) is denoted by "a." Panels B and C show the correlation between
sarcomere stretch and tension. Position number 1 shows extreme sarcomere stretch (as occurs in the
volume-overloaded ventricle) where neither actin filament can interact with the myosin filament; as a result,
tension development is 0. Points 2 and 3 demonstrate situations of maximum actin myosin overlap with
maximal tension production.

Reproduced with permission from: Braunwald E, Ross J Jr, Sonnenblick EH, Mechanisms of Contraction of the Normal and
Failing Heart, 2d ed, Little, Brown, Boston, 1972. Copyright © 1972 Lippincott Williams & Wilkins.

http://www.lww.com
Graphic 63547 Version 9.0
Frank-Starling curves in heart failure

Idealized family of Frank-Starling curves produced by worsening ventricular function in

heart failure. In ventricles with normal cardiac performance, there is a steep and
positive relationship between increased cardiac filling pressures (as estimated from
the LVEDP or pulmonary capillary wedge pressure) and increased stroke volume or
cardiac output (top curve). By comparison, during progression from mild to severe
myocardial dysfunction, this relationship is right shifted (ie, a higher filling pressure is
required to achieve the same cardiac output) and flattened so that continued increases
in left heart filling pressures lead to minimal increases in cardiac output at the possible
expense of pulmonary edema. The onset of mild heart failure results in an initial
reduction in cardiac function (from point A to point B), a change that can be
normalized, at least at rest, by raising the LVEDP via fluid retention (point C). Diuretic
therapy reduces left ventricular filling pressure at the expense of mildly decreased
cardiac output (moving from point C to point B). By comparison, normalization of
stroke volume is not attainable in severe heart failure (bottom curve).

LVEDP: left ventricular end-diastolic pressure.

Graphic 58693 Version 8.0

Systolic versus diastolic dysfunction in heart failure

Pressure-volume loops in normal subjects (in blue) and those with heart failure due to
systolic (left panel) or diastolic (right panel) dysfunction. The pressure-volume loop is
shifted to the right with systolic dysfunction. The end-diastolic pressure is increased
compared with normal (25 versus 10 mmHg in this example), but at a higher
ventricular volume and lower ejection fraction. In contrast, the pressure-volume loop is
shifted to the left with isolated diastolic dysfunction. Contractility is normal in this
setting, but the increase in ventricular stiffness results in an elevated end-diastolic
pressure at a lower left ventricular volume.

Data from: Zile MR. Concepts Cardiovasc Dis 1990; 59:1.

Graphic 79423 Version 2.0

Effect of increasing afterload on cardiac function

Curves relating stroke volume or cardiac to afterload or systemic vascular resistance

(SVR) in normal subjects and those with heart failure and increasing degrees of
ventricular dysfunction. Increasing afterload has little acute effect in normal subjects
but becomes progressively more limiting on cardiac output in HF. Even though the
effect is small with mild HF, lowering afterload is still important over the long-term
because it slows the rate of loss of myocardial function.

Graphic 55742 Version 1.0

Patterns of left ventricular remodeling

The schematic demonstrates the relationship between LVEDV (represented here by the
size of the inner circle) and LV mass (represented here by the size of the shaded region)
for various patterns of remodeling.
RWT  =  LVPW  X  2  /  LVIDD.
With concentric remodeling, LVEDV is normal or reduced, LV mass is normal, and RWT is
increased (and the ratio of LV mass to LVEDV is increased).
With concentric hypertrophy, LVEDV is normal or reduced, LV mass is increased, and RWT
is increased (and the ratio of LV mass to LVEDV is increased).
With eccentric remodeling, LVEDV is increased, LV mass is normal to reduced, and RWT is
normal or reduced (and the ratio of LV mass to LVEDV is normal or reduced).
With eccentric hypertrophy, LVEDV is increased, LV mass is increased, and RWT is
normal or reduced (and the ratio of LV mass to LVEDV is normal or reduced).

LV: left ventricular; LVEDV: LV end-diastolic volume; RWT: relative wall thickness; LVPW: LV
posterior wall thickness at end-diastole; LVIDD: LV internal diastolic dimension.

Courtesy of William Gaasch, MD, Tufts University School of Medicine.

Graphic 87847 Version 5.0

Cardiac remodeling after anterior myocardial infarction

Late ventricular enlargement, or remodeling, resulting from increased circumference and

sphericity, produces a marked increase in volume. The late change in circumference is due
to lengthening of contractile tissue rather than further expansion of the infarcted,
noncontractile segment. The increased sphericity results from a rounding out of the sharp
abnormalities in contour at the margins of the infarct.

Reprinted with permission from the American College of Cardiology, J Am Coll Cardiol 1992; 19:1136.

http://www.elsevier.com/locate/jacc
http://www.sciencedirect.com
Graphic 69944 Version 2.0
Contributor Disclosures
Wilson S Colucci, MD Grant/Research/Clinical Trial Support: Merck [Heart failure]. Jay N Cohn, MD Equity
Ownership/Stock Options: Cardiology Prevention [Screening CVD in asymptomatic individuals]. Other
Financial Interest: Arbor Pharmaceuticals [Royalties - heart failure (isosorbide dinitrate)]. Stephen S
Gottlieb, MD Grant/Research/Clinical Trial Support: Pfizer [Amyloidosis, Heart failure]; Cytokinetics [Heart
failure]; Bristol-Myers Squibb [Heart failure]; BTG International [Renal]. Consultant/Advisory Boards:
Cytokinetics [Heart failure]. Susan B Yeon, MD, JD, FACC Nothing to disclose

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