Circulation. 2006;113:1922-1925
doi: 10.1161/CIRCULATIONAHA.106.620765
(Circulation. 2006;113:1922-1925.)
© 2006 American Heart Association, Inc.
New Molecular Mechanism in Diastolic Heart Failure
Arnold M. Katz, MD;
Michael R. Zile, MD
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 arnold.m.katz{at}dartmouth.edu
Key Words: Editorials diastole heart failure titin cytoskeleton
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Introduction
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In 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 al
1 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.
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Diastolic Dysfunction and DHF
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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 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.
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Heart Failure Versus Asymptomatic LV Dysfunction in SHF and DHF
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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 ß-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 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 Starlings 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.
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Ventricular Architecture in Hypertrophied Hearts
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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).
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Cardiomyocyte Composition in Hypertrophied Hearts
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Concentric and eccentric hypertrophy are associated with different
patterns of activation of growth factors, proto-oncogenes, and
the messenger RNAs that encode sarcomeric, sarcoplasmic reticulum,
and other proteins.
1214 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 ß-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 hypertrophy
19,20 and calcineurin/nuclear factor of activated T cells pathways
in pathological hypertrophy.
21
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Titin Isoforms in SHF and DHF
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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 signaling
25; 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).

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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
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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 content 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.
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Therapeutic Implications
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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.
2931 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 al
1 provides an example of one such target,
because reversal of the titin isoform shift could both improve
function and attenuate maladaptive signal transduction.
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Acknowledgments
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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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Footnotes
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The opinions expressed in this article are not necessarily those
of the editors or of the American Heart Association.
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References
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- van Heerebeck L, Borbély A, Niessen HWM, Bronzwaer JGF, van der Velden J, Stienen GJM, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006; 113: 19661973.[Abstract/Free Full Text]
- Fishberg AM. Heart Failure. Philadelphia, Pa: Lea & Febiger; 1937.
- Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure-abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004; 350: 19531959.[Abstract/Free Full Text]
- Aurigemma GP, Zile MR, Gaasch WH. Contractile behavior in the left ventricle in diastolic heart failure: with emphasis on regional systolic function. Circulation. 2006; 113: 296304.[Free Full Text]
- Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure, part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002; 105: 13871393.[Free Full Text]
- Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure, part II: causal mechanisms and treatment. Circulation. 2002; 105: 15031508.[Free Full Text]
- Hunt SA; American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005; 46: e1e82.[Free Full Text]
- McMurray JJV, Pfeffer MA. Heart failure. Lancet. 2005; 365: 18771889.[CrossRef][Medline]
[Order article via Infotrieve]
- Katz AM. Evolving concepts of heart failure: cooling furnace, malfunctioning pump, enlarging muscle: part II: hypertrophy and dilatation of the failing heart. J Cardiac Fail. 1998; 4: 6781.[Medline]
[Order article via Infotrieve]
- Gerdes AM. Cardiac myocyte remodeling in hypertrophy and progression to failure. J Cardiac Fail. 2002; 8 (suppl): S264S268.[CrossRef][Medline]
[Order article via Infotrieve]
- Russell B, Motlagh GHG, Ashley WW. Form follows function: how muscle shape is regulated by work. J Appl Physiol. 2000; 88: 11271132.[Abstract/Free Full Text]
- Calderone A, Takahashi N, Izzo NJ Jr, Thaik CM, Colucci WS. Pressure- and volume-induced left ventricular hypertrophies are associated with distinct myocyte phenotypes and differential induction of peptide growth factor mRNAs. Circulation. 1995; 92: 23852390.[Abstract/Free Full Text]
- Horban A, Kolbeck-Ruhmkorff C, Zimmer HG. Correlation between function and proto-oncogene expression in isolated working rat hearts under various overload conditions. J Mol Cell Cardiol. 1997; 29: 29032914.[CrossRef][Medline]
[Order article via Infotrieve]
- Modesti PA, Vanni S, Bertolozzi I, Cecioni I, Polidori G, Paniccia R, Bandinelli B, Perna A, Liguori P, Boddi M, Galanti G, Serneri GG. Early sequence of cardiac adaptations and growth factor formation in pressure- and volume-overload hypertrophy. Am J Physiol Heart Circ Physiol. 2000; 279: H976H985.[Abstract/Free Full Text]
- Dorn GW II, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest. 2005; 115: 527537.[CrossRef][Medline]
[Order article via Infotrieve]
- Katz AM. Physiology of the Heart. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006.
- Yamamoto K, Dang QN, Maeda Y, Huang H, Kelly RA, Lee RT. Regulation of cardiac myocyte mechanotransduction by the cardiac cycle. Circulation. 2001; 103: 14591464.[Abstract/Free Full Text]
- Scheuer J, Buttrick P. The cardiac hypertrophic responses to pathologic and physiologic loads. Circulation. 1985; 75 (part 2): I-63I-68.
- McMullen JR, Shioi T, Huang W-Y, Zhang L, Tarnavski O, Bisping E, Schinke M, Kong S, Sherwood MC, Brown J, Riggi L, Kang PM, Izumo S. The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase (p100
) pathway. J Biol Chem. 2004; 279: 47824793.[Abstract/Free Full Text]
- Konhilas JP, Widegren U, Allen DL, Paul AC, Cleary A, Leinwand LA. Loaded wheel running and muscle adaptation in the mouse. Am J Physiol Heart Circ Physiol. 2005; 289: H455H465.[Abstract/Free Full Text]
- Wilkins BJ, Dai Y-S, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, Molekenitn JD. Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res. 2004; 94: 11101118.
- Lim CC, Sawyer DB. Modulation of cardiac function: titin springs into action. J Gen Physiol. 2005; 125: 249252.[Free Full Text]
- Fukuda N, Wu Y, Nair P, Granzier H. Phosphorylation of titin modulates passive stiffness of cardiac muscle in a titin isoform-dependent manner. J Gen Physiol. 2005; 125: 249252.[Free Full Text]
- Borbély A, van der Velden J, Papp Z, Bronzwaer JGF, Edes I, Stienen GJ, Paulus WJ. Cardiomyocyte stiffness in diastolic heart failure. Circulation. 2005; 111: 774781.[Abstract/Free Full Text]
- Granzier HL, Labeit S. The giant protein titin: a major player in myocardial mechanics, signaling and disease. Circ Res. 2004; 94: 284295.[Abstract/Free Full Text]
- LeWinter MM. Titin isoforms in heart failure: are there benefits to supersizing? Circulation. 2004; 110: 109111.[Free Full Text]
- Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL. Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation. 2004; 110: 155162.[Abstract/Free Full Text]
- Katz AM, Katz PB. Homogeneity out of heterogeneity. Circulation. 1989; 79: 712717.[Free Full Text]
- Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, Olofsson B, Östergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003; 362: 777781.[CrossRef][Medline]
[Order article via Infotrieve]
- Little WC, Wesley-Farrington DJ, Hoyle J, Brucks S, Robertson S, Kitzman DW, Cheng CP. Effect of candesartan and verapamil on exercise tolerance in diastolic dysfunction. J Cardiovasc Pharmacol. 2004; 43: 288293.[CrossRef][Medline]
[Order article via Infotrieve]
- Little WC, Zile MR, Klein A, Appleton CP, Kitzman DW, Wesley-Farrington DJ. Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol. In press.
- Gaasch WH, Zile MR. Left ventricular diastolic dysfunction and diastolic heart failure. Annu Rev Med. 2004; 55: 373394.[CrossRef][Medline]
[Order article via Infotrieve]
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