Download Arnold M. Katz and Michael R. Zile 2006;113:1922-1925 doi: 10.1161/CIRCULATIONAHA.106.620765

New Molecular Mechanism in Diastolic Heart Failure
Arnold M. Katz and Michael R. Zile
Circulation. 2006;113:1922-1925
doi: 10.1161/CIRCULATIONAHA.106.620765
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Editorial
New Molecular Mechanism in Diastolic Heart Failure
Arnold M. Katz, MD; Michael R. Zile, MD
I
n contrast to systolic heart failure (SHF), for which
knowledge of pathophysiology and therapy has advanced
rapidly over the past decade, little is known about
diastolic heart failure (DHF). The article by van Heerebeek et
al1 in this issue of Circulation that describes an abnormal
distribution of titin isoforms in DHF may herald a new
approach to understanding the pathophysiology of this
syndrome.
Article p 1966
Recognition of 2 forms of heart failure is not new; almost
70 years ago, Fishberg2 described “those forms of cardiac
insufficiency which are due to inadequate diastolic filling of
the heart (hypodiastolic failure) [and] the far more common
ones in which the heart fills adequately but does not empty to
the normal extent (hyposystolic failure)” (p 23). This distinction has stood the test of time, because there is a growing
consensus that these 2 clinical syndromes differ in epidemiology, demographics, and origin. Because DHF and SHF
represent subgroups of patients with heart failure, they share
many clinical features, notably the hemodynamic findings,
but it is now clear that they are caused by different pathophysiological mechanisms. Hearts in SHF are characterized by
eccentric hypertrophy, progressive left ventricular (LV) dilation, and abnormal LV systolic properties, whereas in DHF,
the hearts generally exhibit concentric hypertrophy, normal or
reduced LV volume, concentric remodeling, and abnormal
diastolic function.3,4 In addition, cardiomyocyte size, shape,
and molecular composition differ in these 2 syndromes.
Diastolic Dysfunction and DHF
Diastolic dysfunction refers to mechanical and functional
abnormalities present during relaxation and filling, whereas
DHF refers to clinical syndromes in which patients with heart
failure have little or no ventricular dilatation and significant,
often dominant diastolic dysfunction. Diastolic dysfunction
can be quantified with indices of LV pressure decline and
filling. Abnormal pressure decline is characterized by decreased peak ⫺dP/dt, prolonged isovolumic time constant (␶),
and increased isovolumic relaxation time. Abnormal filling is
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the University of Connecticut School of Medicine, Farmington,
Conn, and Dartmouth Medical School, Lebanon, NH (A.M.K.); and the
Division of Cardiology and the Gazes Cardiac Research Institute,
Department of Medicine, Medical University of South Carolina and RHJ
Department of Veterans Affairs Medical Center, Charleston, SC
(M.R.Z.).
Correspondence to Arnold M. Katz, MD, 1592 New Boston Rd, PO Box
1048, Norwich, VT 05055-1048. E-mail [email protected]
(Circulation. 2006;113:1922-1925.)
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.620765
characterized by slow and incomplete filling, increased atrial
contribution to filling, and increased chamber stiffness, which
can be caused by abnormalities in both cardiomyocytes and
the extracellular matrix.5,6 Changes in calcium homeostasis,
energetics, myofilaments, and the cytoskeleton can impair
cardiomyocyte relaxation and increase stiffness, as can increases in the content of extramyofilament cytoskeletal proteins, such as microtubules, and abnormalities that involve
intramyofilament cytoskeletal proteins like titin. At the extracellular matrix level, changes in the amount, composition,
and geometry of such matrix proteins as collagen and elastin
can alter LV stiffness. By causing decreased or delayed
relaxation, slow or incomplete filling, and increased diastolic
stiffness, these abnormalities can lead to the development of
DHF.
Heart Failure Versus Asymptomatic LV
Dysfunction in SHF and DHF
Intermittent symptomatic exacerbations and remissions are
common in patients with both SHF and DHF. This unstable
clinical course reflects an interplay between the underlying
abnormalities in the heart and exacerbating factors that can
convert asymptomatic LV dysfunction to symptomatic heart
failure. Systolic dysfunction, which reduces the ability of the
LV to develop tension and shorten and which generally leads
to eccentric LV hypertrophy, is due most commonly to
myocardial infarction and, less frequently, dilated cardiomyopathy. Impaired ejection and LV dilatation in SHF reduces
ejection fraction, the ratio of stroke volume and end-diastolic
volume (EDV). Depending on exacerbating factors such as
increased preload (eg, fluid retention), increased afterload
(eg, peripheral vasoconstriction), and arrhythmias (eg, atrial
fibrillation), systolic dysfunction may or may not be associated with symptomatic heart failure. Until about a decade
ago, treatment of SHF sought to alleviate the hemodynamic
consequences of these exacerbating factors; diuretics were
given to lower preload and vasodilators to reduce afterload.
However, most forms of therapy that improve prognosis in
SHF are now recognized to slow, and sometimes reverse, the
progressive increase in EDV (“remodeling”) in the dilated
LV of these patients. The ability of ␤-adrenergic receptor
blockers to inhibit remodeling is especially marked, but
similar benefit has been reported after administration of
angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, and cardiac resynchronization therapy.7,8
Although the exacerbating factors that worsen symptoms
in DHF are similar to those in SHF, the underlying abnormalities are quite different. In DHF, the most common
architectural abnormalities are concentric LV hypertrophy or
concentric remodeling, both of which are frequently caused
by chronic pressure overload (eg, hypertension). Changes
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Katz and Zile
New Molecular Mechanism in Diastolic Heart Failure
1923
Titin (red) extends from the Z-line to the center of the thick filaments, where it is linked to
myosin by myosin binding protein C
(orange). Other proteins that interact with titin
include M-protein, myomesin, obscurin, and
ankyrin, which are found in the M-bands that
link adjacent thick filaments in the center of
the A-band. Regions of the titin molecule
within the A-band are quite rigid, whereas
those in the I-band are more elastic. “Hot
spots” in titin also participate in signal transduction (shaded rectangles); these are
labeled “Z-line signaling,” “M-band-based
signaling,” and “Central I-band-based signaling.” Modified from Katz.16
associated with aging also play a major role in DHF, but
much remains to be learned about such age-related changes as
decreased rates of LV relaxation and filling and increases in
LV and arterial stiffness. What is clear is that changes in LV
structure and function that accompany aging make patients
with hypertension, diabetes mellitus, or coronary heart disease more vulnerable to the development of DHF.
The structural and functional abnormalities that cause
diastolic dysfunction make it especially difficult for the hearts
of patients with DHF to meet the challenges posed by an
acute increase in preload or afterload or an arrhythmia. This
is because diastolic dysfunction impairs the ability of the LV
to fill, which, in addition to increasing diastolic pressure,
makes it difficult for Starling’s law to enhance cardiac
performance. As a result, diastolic dysfunction sets the stage
for rapid, often precipitous increases in pulmonary venous
pressure. This can explain why patients with abnormal
diastolic function who are asymptomatic under most conditions can develop severe acute pulmonary edema after a salty
meal, a rapid increase in arterial blood pressure, or the onset
of atrial fibrillation.
Ventricular Architecture in
Hypertrophied Hearts
Two patterns of cardiac enlargement, initially recognized at
the beginning of the 19th century,9 are now generally referred
to as eccentric hypertrophy, in which EDV is increased, and
concentric hypertrophy, in which wall thickness is increased
and EDV can be reduced or unchanged. These architectural
patterns are now known to reflect differences in cardiomyocyte size and shape; in eccentric hypertrophy, enlargement is
due largely to increased cell length, whereas cross-sectional
area is increased in concentric hypertrophy.10 These morphological differences appear to result from sarcomere addition
at the ends of the myocytes in eccentric hypertrophy (sarcomere replication in series) and throughout the myocyte in
concentric hypertrophy (sarcomere replication in parallel).11
Perhaps the most striking difference between SHF and
DHF is the tendency of EDV to increase in SHF, whereas
progressive dilatation, by definition, does not occur in DHF.
This distinction, which can be attributed to activation of
different proliferative signaling mechanisms, has important
implications, because therapy that improves prognosis in SHF
may not slow progression in DHF (see below).
Cardiomyocyte Composition in
Hypertrophied Hearts
Concentric and eccentric hypertrophy are associated with
different patterns of activation of growth factors, protooncogenes, and the messenger RNAs that encode sarcomeric,
sarcoplasmic reticulum, and other proteins.12–14 Cardiomyocyte elongation and thickening result from activation of
different signal transduction pathways,15,16 and mechanical
stresses applied during systole and diastole can activate
different proliferative signaling pathways.17 Exercise-induced
“physiological” hypertrophy is accompanied by increased
expression of the adult ␣-myosin heavy chain isoform and a
higher content of sarcoplasmic reticulum, whereas expression
of fetal ␤-myosin heavy chain is increased and the content of
sarcoplasmic reticulum reduced in the “pathological” hypertrophy associated with chronic pressure overload.18 These
differences have recently been found to be associated with
activation of phosphoinositide 3⬘-OH kinase/phosphatidylinositol triphosphate/Akt pathways in physiological hypertrophy19,20 and calcineurin/nuclear factor of activated T cells
pathways in pathological hypertrophy.21
Titin Isoforms in SHF and DHF
Evidence that cardiomyocytes in SHF and DHF express
different gene products is provided by van Heerebeek et al,1
who examined the titin isoforms in the hearts of patients with
these 2 clinical syndromes. Titin is a huge cytoskeletal
protein that extends from the Z-lines to the center of the thick
filament (Figure), where it contributes to the high resting
stiffness of the myocardium.22 Phosphorylation of titin by
protein kinase A decreases its stiffness, which, by increasing
LV diastolic compliance, helps the heart to fill during
sympathetic stimulation.23,24 In addition to its mechanical
function, titin contains “hot spots” that participate in cell
signaling25; the latter could allow this protein to mediate
proliferative responses that generate specific hypertrophy
phenotypes when hearts are subjected to different mechanical
stresses (see above).
Mammalian hearts contain either of 2 titin isoforms, called
N2BA and N2B, or both isoforms.26 A key difference is that
the N2B isoform is stiffer than the N2BA isoform, so that it
is not surprising that N2B tends to predominate in stiffer
ventricles, whereas N2BA occurs in more compliant hearts.
Titin isoform expression changes in response to chronic
overloading in experimental animals, and an increased con-
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1924
Circulation
April 25, 2006
tent of the less stiff N2BA isoform has been reported in
human dilated cardiomyopathy.27 The reduced ratio between
the N2BA and N2B titin isoforms in DHF found by van
Heerebeek et al1 suggests an additional role for titin isoform
shifts, because the greater abundance of the stiffer N2B
probably contributes to the high diastolic stiffness in DHF.
The role of the cytoskeleton in mediating the proliferative
signals that adapt form to function11,25,28 could, by activating
specific transcriptional pathways, help explain how different
patterns of cellular deformation induce various architectural
forms of hypertrophy. Signals mediated by different patterns
of titin deformation could, for example, allow pressure
overload to cause concentric hypertrophy (as occurs in aortic
stenosis, which increases systolic stress) and volume overload
to cause eccentric hypertrophy (as occurs in aortic insufficiency, which increases diastolic stress). An additional implication of evidence that different titin isoforms are expressed in SHF and DHF1 is that the titin isoform might
contribute to the differences in ventricular architecture in
SHF and DHF and the absence of progressive LV dilatation
in DHF.
Therapeutic Implications
There are few clinical trials to help guide the treatment of
DHF. Several small studies have shown that an angiotensin
receptor blocker improves exercise tolerance, and one large,
randomized clinical trial (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity
[CHARM]-Preserved) suggests that an angiotensin receptor
blocker reduces hospitalization for DHF.29 –31 Most treatment
strategies for DHF, however, attempt to alleviate congestive
symptoms by reducing LV preload and afterload, attenuating
such exacerbating factors as tachycardia and ischemia, and
controlling blood pressure in hypertensive patients. It is clear,
however, that strategies for DHF should also target the
underlying structural, functional, and molecular mechanisms,
but success in these efforts may be difficult to achieve,
because many pathological mechanisms lead to DHF.32 This
situation differs from SHF, for which clinical trials have
shown that, with the exception of gene polymorphisms, there
are few significant differences in the long-term responses of
various clinical subgroups to therapy. This uniformity can be
explained if a major benefit of effective long-term therapy in
SHF is to inhibit progressive cardiomyocyte elongation.
Because this therapeutic target is absent in DHF, in which
progressive dilatation is not an important cause of clinical
deterioration, optimal therapy may have to address the
specific pathophysiology that operates in each patient. The
titin abnormality described by van Heerebeek et al1 provides
an example of one such target, because reversal of the titin
isoform shift could both improve function and attenuate
maladaptive signal transduction.
Disclosures
Dr Zile has received grants from the Research Service of the
Department of Veterans Affairs (PO1-HL-48788) and the National
Heart, Lung, and Blood Institute (MO1-RR-01070-251). Dr Katz has
no disclosures.
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KEY WORDS: Editorials
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