KARDIOLOGI KLINIK

Alterations in Ventricular
Structure: Role of Left Ventricular
Remodeling and Reverse
Remodeling in Heart Failure

Ida Bagus Ananta Wijaya

OVERVIEW
Process of LV remodeling arises from:
• Changes in biology of the cardiac myocyte
• Myocardial histological changes  resulted from volume of myocyte
and nonmyocyte components of the myocardium
• Changes in the geometry and architecture of the LV chamber

Reversal remodelling?  characterized anatomically by a return in LV

volume and mass toward normal values  represent summation of a series
of integrated biologic changes in cardiac myocyte size and function, as well as
modifications in LV structure and organization
 LV Remodelling terms…
Describes the changes in
mass, volume, shape,
and composition
observed in the LV in
response to mechanical
stimulation and systemic
neurohormonal
activation
 Alterations in Myocyte Biology
(1) cell hypertrophy
(2) reactivation of fetal genes (including β-adrenergic desensitization)
(3) Loss of myofibrils and progressive disarray of the cytoskeleton
(4) Changes in excitation-contraction coupling leading to alterations
in the contractile properties of the myocyte
(5) Modifications of myocyte metabolism
Early stage: increases in the number of myofibrils and
mitochondria and enlargement of mitochondria and
nuclei. Muscle cells are larger than normal, but cellular
organization is largely preserved

Increases in the size or number of specific organelles,

such as mitochondria, along with irregular addition of
new contractile elements in localized areas of the cell,
result in subtle abnormalities of cellular organization
and contour

More obvious disruptions in cellular organization, such

as markedly enlarged nuclei with highly lobulated
membranes, which displace adjacent myofibrils and
cause breakdown of normal Z-band registration

Late stage of hypertrophy: loss of contractile elements

with marked disruption of Z bands, severe disruption of
the normal parallel arrangement of the sarcomeres,
deposition of fibrous tissue, and dilation and increased
tortuosity of T tubules
Cardiac myocyte hypertrophy  reactivation of portfolios of genes (fetal gene
program)

Reactivation of fetal gene program, accompanied by decreased expression of a

number of genes that are normally expressed in the adult heart (i.e gene for the
β1 adrenergic receptor  β-adrenergic desensitization  contribute to the
contractile dysfunction that develops in the failing myocyte in many other
ways.

The stimuli for the genetic reprogramming of the myocyte include mechanical
stretch/strain of the myocyte, neurohormones (e.g., NE, angiotensin II),
inflammatory cytokines (e.g., tumor necrosis factor [TNF], interleukin-6 [IL-
6]), other peptides and growth factors (e.g., ET), and reactive oxygen species
(e.g.,
superoxide, NO).
The cytoskeleton of the myocyte  consists of actin, the intermediate filament
desmin, the sarcomeric protein titin, and α- and β-tubulin that form
microtubules by polymerization. Vinculin, talin, dystrophin, and spectrin
represent a separate group of membrane-associated proteins.

The failing myocyte shows alterations in cytoskeletal and membrane-associated

proteins implicated in the pathogenesis of HF.

This is accompanied by alterations in excitation-contraction coupling  closely

linked to myocardial contractile dysfunction.

These changes include modification in the abundance of critical Ca2+ regulatory

proteins including sarcoplasmic endoreticular Ca2+ ATPase (SERCA), ryanodine
receptor (RyR), L-type calcium channel (LTCC), and sarcolemmal Na+/Ca2+
exchanger (NCX)
 Alteration in Myocardium
The alterations/changes that occur in failing myocardium may be categorized
broadly into:
1. Alteration within the cardiac myocyte compartment  necrosis and
apoptosis

2. Alteration in the volume and composition of the extracellular matrix (ECM)

• changes in overall collagen content,
• changes in the relative contents of different collagen subtypes
• changes in collagen cross-linking
• modifications of the connections between cells and the ECM via
integrins

3. Changes in the myocardial microvasculature

• Strong relationship between cardiac myocytes and their blood supply.
• A mismatch between cardiac myocyte growth and blood supply 
contractile dysfunction and cell death (for example, in patients with
dilated cardiomyopathy that have a reduced myocardial capillary
density)
Focus on changes in collagen cross-linking

Loss of cross-linking of the fibrillar

collagen  associated with progressive
LV dilation following myocardial injury

The increased fibrous tissue  lead to

increased myocardial stiffness 
decreased myocardial shortening for a
given degree of afterload.

Myocardial fibrosis may provide the structural substrate for atrial and ventricular
arrhythmias  contributing to sudden death.

Many of the classical neurohormones (e.g., angiotensin II, aldosterone) and cytokines
(ET, transforming growth factor-β [TGF-β], cardiotrophin-1) that are expressed in HF are
sufficient to provoke fibroblast activation.

The use of angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and aldosterone

receptor antagonists  associated with a decrease in myocardial fibrosis in
experimental HF models.
Alteration in Left Ventricular Geometry
Changes that occur in the biology of the cardiac myocyte and the myocardium
(cardiac myocytes and ECM)  lead to progressive LV dilation and increased
sphericity of the ventricle.

High end-diastolic wall stress might be expected to lead to:

• hypoperfusion of the subendocardium, with resultant ischemia and worsening of
LV function
• increased oxidative stress with resultant activation of families of genes that are
sensitive to free radical generation (e.g., TNF and interleukin-1β)
• Sustained expression of stretch-activated genes (angiotensin II, endothelin, and
TNF) and/or stretch activation of hypertrophic signaling pathways.

Increasing LV dilatation and sphericity  tethering of the papillary muscles, resulting

in incompetence of the mitral valve and the development of “functional mitral
regurgitation.”

Mitral regurgitation  results in further hemodynamic overloading of the ventricle.

Expected to lead to:
• decreased forward cardiac output
• increased LV dilation (stretch)
• increased hemodynamic overloading
 REVERSE LV REMODELLING?
First used to describe the leftward shift in the LV end-diastolic pressure-
volume curve of the failing heart following hemodynamic unloading with a
ventricular assist device
 Reverse LV Remodeling in Clinical
Settings

Reverse remodeling is observed in a variety of clinical settings, as shown in the middle ring of
the diagram.

The segments illustrated in the outermost ring highlight the pathophysiologic processes
implicated by reverse remodeling in each particular clinical setting.
Favorable changes of the LV following pharmacologic and
device therapies that lead to reverse remodeling
Summary of Changes in excitation-contraction Coupling
in Cardiac Myocytes (assisted with LVAD)
Trial Results of pharmacological and device therapy on
reversing cardiac remodelling
 Myocardial Recovery and Myocardial Remission

Term myocardial recovery should be used to describe the rare

normalization of the molecular, cellular, myocardial, and LV geometric
changes that are associated with freedom from future HF events

Term myocardial remission should be used to refer to the normalization of

the molecular, cellular, myocardial, and LV geometric changes that
provoke cardiac remodeling that are insufficient to prevent the
recurrence of HF in the face of normal and/or perturbed hemodynamic
loading conditions
 Myocardial Recovery and Myocardial Remission

Although the biologic differences between myocardial recovery and

myocardial remission are not known, it bears emphasis that, as described
above, in most instances, reverse LV remodeling normalization of the HF
phenotype does not lead to a “normal” heart

Why?
1. Gene expression profiling studies have shown that only
approximately 5% of genes that are dysregulated in failing hearts
revert back to normal following LVAD support, despite typical
morphologic and functional responses to LVAD support
2. Calcium-saturated force generation is still less than in myocytes
from nonfailing controls, despite reversal of cardiac myocyte
hypertrophy
3. Although the LV EDPVRs of LVAD-supported hearts are shifted
leftward, and overlap those found in nonfailing ventricles, the ratio
of LV wall thickness-to-LV wall radius does not return to normal
despite normalization of LV chamber geometry
 Summary

The failing heart undergoes a number of maladaptive changes in LV structure

and function that contribute to disease progression in the clinical syndrome of
HF.

Numerous clinical and epidemiologic studies have also suggested that HF is

potentially reversible and that the heart is capable of undergoing favorable
reversal of the changes in LV structure and function that are associated with
stabilization of the clinical syndrome of HF.

Normalization of the HF phenotype during reverse LV remodeling typically

does not signify that the cellular/molecular biology and physiology of these
hearts actually becomes normal. While this model explains the
epidemiological data indicating that patients with recovered LVEF almost
univocally remain at increased risk of future cardiovascular events, the
molecular and mechanistic basis of the difference between reverse remodeled
and naïve hearts remain largely unknown