doi: 10.1161/01.RES.0000129254.25507.d6
© 2004 American Heart Association, Inc.
Reviews |
What Mechanisms Underlie Diastolic Dysfunction in Heart Failure?
From the Division of Cardiology (D.A.K.), Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Md; and the Institute for Cardiovascular Research (W.J.P., J.G.F.B.), Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
Correspondence to David A. Kass, Johns Hopkins Medical Institutions, Medicine, Cardiology, 500 Halstead, Baltimore, MD 21224. E-mail dkass{at}jhmi.edu
This Review is part of a thematic series on Unanswered Questions in Heart Failure, which includes the following articles:
Is Depressed Contractility Centrally Involved in Heart Failure?
What is the Role of B-Adrenergic Signaling in Heart Failure?
What Mechanisms Underlie Diastolic Dysfunction in Heart Failure?
What Causes Sudden Death in Heart Failure?
Is Abnormal Cell Growth and Hypertrophy the Cause of Heart Failure?
Does Energy Starvation Cause Heart Failure
Steven Houser Guest Editor
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Abstract |
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Abnormalities of diastolic function are common to virtually all forms of cardiac failure. However, their underlying mechanisms, precise role in the generation and phenotypic expression of heart failure, and value as specific therapeutic targets remain poorly understood. A growing proportion of heart failure patients, particularly among the elderly, have apparently preserved systolic function, and this is fueling interest for better understanding and treating diastolic abnormalities. Much of the attention in clinical and experimental studies has focused on relaxation and filling abnormalities of the heart, whereas chamber stiffness has been less well studied, particularly in humans. Nonetheless, new insights from basic and clinical research are helping define the regulators of diastolic dysfunction and illuminate novel targets for treatment. This review puts these developments into perspective with the major aim of highlighting current knowledge gaps and controversies.
Key Words: myocardium • dilated cardiomyopathy • heart failure • hypertrophy • compliance • diastole • relaxation
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Introduction |
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The heart spends more than half its time in diastole (relaxing and then filling to prepare for the next ejection). Although abnormalities of diastolic function are well recognized and common to virtually all forms of heart failure, just how they affect basal and reserve function and their relative role in clinical heart failure remain unclear. There are a number of reasons for this. First, diastole assessment ideally requires invasive measurements that are nontrivial to obtain, whereas noninvasive surrogates often reported in clinical studies reflect integrative properties that lack specificity. Second, relatively few animal models recapitulate human diastolic disease, particularly chamber stiffening, which is often normal in murine models despite extensive matrix, myofibrillar, or signaling abnormalities. Third, there are few if any targeted treatments that can specifically test the impact of altering diastolic function on heart failure pathophysiology and outcome. Last, diastolic function has been less amenable to reductionist approaches given the potent roles that chamber geometry, loading (both intrinsic and extrinsic to myocytes), extracellular matrix, and myocardial perfusion all bring to bear.
Another problem is that there is no single definition for diastolic dysfunction; many features can be altered, and any one change or their combination is typically called diastolic dysfunction, although the pathophysiology and functional significance varies greatly. Thus, the term is used to describe slowed force (or pressure) decay and cellular relengthening rates, increased (or decreased) early filling rates and deceleration, elevated or steeper diastolic pressure–volume (PV) relations, and filling-rate dependent pressure elevation (viscoelasticity). Clinically, the most common manifestation is an elevated end-diastolic pressure (EDP) and altered filling patterns, but neither of these identifies specific features of diastolic dysfunction.
Despite these difficulties, it remains widely presumed that diastolic abnormalities are important to heart failure pathophysiology, and this is driving new research to elucidate the biochemical and structural mechanisms that underlie it, clarify its role to clinical heart failure, and develop targeted treatments for it. Important insights are being gleaned from genetically engineered models that facilitate molecular hypothesis testing in the intact chamber. Clinical epidemiology is fueling interest because many patients with cardiac failure present with preserved ejection fraction, which has rightly or wrongly focused attention on diastolic dysfunction.1,2
This article reviews recent insights into diastolic dysfunction with heart failure, focusing on unresolved or controversial areas in need of further research. We divide our discussion into 2 primary components: relaxation and diastolic stiffness defined by the length–tension or PV relationship. We avoided discussion of diastolic filling patterns and tissue velocities because these are more integrative in nature and have been dealt with in recent reviews.2–5
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How Do Myocytes Control Relaxation? |
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Myocardial relaxation requires that strongly bound actin–myosin filaments return to a low–force-generating state. Anything that interferes with cross-bridge detachment or with preceding calcium removal from the cytosol has the potential to delay relaxation. This includes prolongation of the Ca2+-transient because of reduced resequestration into the sarcoplasmic reticulum (SR), abnormal extrusion by the sodium/calcium exchanger (NCX), interference with cross-bridge uncoupling by abnormal high-energy phosphate metabolism, and abnormalities of the contractile proteins themselves affecting their interaction or Ca2+ sensitivity. Furthermore, in intact muscle, force decay is also mediated by the recovery of stored elastic energy generated during systolic contraction, and this can be blunted by heart failure as well. Although much has been learned about each of these processes, many questions about their interplay, regulation, and relative role to relaxation remain unanswered.
Alterations in myocyte–calcium-handling proteins, including the sarcoplasmic reticular Ca2+-ATPase (SERCA2a) and its modulator phospholamban (PLB),6–9 the SR–Ca2+ release channel and its modulator FK-506 binding protein 12.6 (FKBP12.6), and NCX have all been implicated in altering the calcium transient in failing hearts and contributing to delayed relaxation. SR–Ca2+ uptake activity declines with heart failure often coupled to reduced gene and protein expression of both enzymes.6,10 Both proteins can be serine-phosphorylated by protein kinase A (PKA), and reduced phosphorylation of PLB11 (associated with increased protein phosphatase [PP1]12,13) appears important for relaxation delay. PLB can also be phosphorylated by protein kinase C (PKC-
),8 although higher levels of PKC- may reduce phosphorylation in part by activating PP1.14 The role of SERCA2a phosphorylation by PKA remains little understood,15 and recent exploration into the molecular nature of PLB–SERCA2a interaction16 suggests that additional sites may also affect their molecular coupling. Both proteins have been modified by gene transfer or genetic engineering, confirming their role in relaxation. Gene transfer with SERCA2a or a negative PLB–mutant improves relaxation.17–19 Removal of PLB deletes inhibitor and potential facilitator functions,20 and the net result can vary depending on the physiologic conditions. For example, restoration of wild-type PLB to PLB–null mice enhances rate-dependent relaxation yet has little effect on basal rates.21
In addition to SERCA2a and PLB, alterations in the ryanodine-sensitive Ca2+ release channel may play a role. PKA hyperphosphorylation and reduced levels of FKBP12.6-stabilizing protein have been suggested to induce diastolic SR–Ca2+ leakage,22,23 and this can be reduced by ß-adrenergic blockade.24,25 However, the role and mechanism for PKA modulation of this process in normal tissue has been recently questioned,26,27 and direct evidence that this abnormality can delay relaxation remains lacking. Finally, NCX upregulation in failing myocardium28–30 offset depressed SR–Ca2+ uptake by working in the forward mode to extrude intracellular Ca2+.29 However, Ca2+ entry via the NCX mediated by reduced-peak Ca2+, higher sodium, and action potential prolongation can delay relaxation.30,31 As yet, we do not know whether NCX–Ca2+ flux balance indeed modifies diastolic relaxation in heart failure or in what direction.
Relaxation can also be potently modified by changing the interaction of Ca2+ with the regulatory thin filaments or by modifying the proteins themselves.32 For example, genetic replacement of troponin I (TnI) to a skeletal isoform that cannot be PKA phosphorylated33 or overexpression of a TnI that behaves as if constituitively phosphorylated at PKA sites34 lengthens and shortens relaxation, respectively. Pharmacological manipulation of force–Ca2+ dependence by small molecule inhibitors can favor formation of tightly bound cross-bridges,35,36 although in isolated preparations, they also increase force at diastolic Ca2+ levels.37 The xanthine oxidase inhibitor allopurinol also shifts the force–Ca2+ curve leftward38 but does so without increasing sensitivity at diastolic Ca2+ levels.39 Much of this mechanism is still unknown.
Relaxation can also be delayed by alterations in the molecular motors themselves. One example is the ß- (versus -) myosin heavy chain (MHC) isoform,40 which prolongs force rise and relaxation, although this has less impact in larger mammals and humans because the ß-MHC isoform dominates under normal conditions. Another example is myosin mutations that directly affect its binding to actin. Mice harboring the heterozygous mutation R403Q in the -MHC display profound prolongation of relaxation even at a young age when there is no hypertrophy, myofibrillar disarray, or altered systolic function.41,42 With aging, these mice evolve hyperdynamic contraction with intracavitary pressure gradients, whereas relaxation remains profoundly delayed.41 Importantly, these animals do not manifest heart failure or have elevated diastolic pressures, reminding us that the link between prolonged relaxation and diastolic failure is far from automatic. More research is needed to identify structure–function relationships in myofilament and thin-filament regulatory proteins that can determine relaxation.
When hearts contract below their unstressed volume (myocyte slack length), they store elastic energy that is then released in the next diastolic period. This process, called elastic recoil, manifests as negative pressure for a given end-systolic volume if cardiac filling is abruptly prevented.43–45 Elastic recoil appears diminished in cardiac failure,46 which may relate to changes in structural or biochemical changes in the extracellular matrix, the inability of the heart to contract below equilibrium (unstressed) volume, or isoform changes in sarcomeric proteins, including titin.47,48
A final comment should be made about how relaxation delay is measured because conclusions can vary greatly depending on the mathematical approach used. Decay waveforms (whether derived from force, pressure, or cell length) are most often fit to monoexponential decay curves. However, this is an arbitrary choice because there is no a priori mechanism underlying this particular waveform. Although the monoexponential fit is reasonable in many instances, it is less so in dilated failing hearts,6 and its use in this setting yields artificially prolonged relaxation estimates and amplifies an apparent dependence of relaxation delay on EDP.49 Alternative approaches, such as provided by a logistic model, provide better fits to the failing heart pressure decline data49,50 and deserve wider consideration.
Despite the identification of numerous molecular mechanisms that have the potential to alter muscle relaxation mechanics, their interaction and quantitative impact on relaxation remains poorly understood. More studies are needed that incorporate targeted molecular manipulations with relevant muscle and chamber loading to help narrow this information gap. Development of tools to specifically enhance relaxation would also help in determining its net impact on diastolic dysfunction in the failing heart.
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How Does Cardiac Load Influence Relaxation? |
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The failing heart is exposed to increased chamber loading stemming from high filling volume (preload) and wall stress and arterial impedance (afterload). Both types of load can influence basal left ventricular (LV) relaxation rate,51 but their effects may be more relevant during neurohormonal stimulation. In heart transplant patients, lusitropic effects of sympathetic stimulation during exercise are blunted as preload increases,52,53 whereas increasing papillary muscle preload stretch to high levels also blocks enhanced relaxation from ß-adrenergic stimulation.54 This could reflect a balance of enhanced myofilament calcium sensitivity at higher preloads offset by enhanced shortening below slack-length–enhancing elastic recoil by a titin-dependent mechanism55 In intact human hearts, preload modulation of relaxation has seemed increased by heart failure, but this result has been shown to depend mostly on how relaxation is mathematically assessed.49 Studies using methods that more accurately index pressure decay in these patients find little impact of preload.
Cardiac afterload (particularly that related to arterial resistance and wave reflections) more consistently affects relaxation, yet underlying mechanisms and the significance of this interaction in vivo remain unclear. Studies in intact hearts using abrupt (within-cycle) occlusion of the aorta have imposed loads during late systole at the identical preload and found a nonlinear relation between end-systolic pressure and relaxation rate.56,57 The timing of load increase is important, with loads applied later in systole having a greater effect.58 Clinical studies have measured relaxation delay during isometric hand–grip-induced hypertension,59 although marked reduction of LV afterload in patients with aortic stenosis slowed LV pressure decay,60 so this relationship is complex and multifactorial. More recent data suggest that PKA phosphorylation of TnI may play a role in the afterload–relaxation interaction.34 Mice overexpressing a mutant TnI that behaved as if constituitively phosphorylated at both PKA sites had less afterload-induced relaxation delay than controls, and this was recapitulated in wild-type mice by infusion of isoproterenol to stimulate PKA. The result is intriguing given evidence of reduced PKA–TnI phosphorylation in heart failure61,62 and increased relaxation load sensitivity in this condition. Because high afterload is common in heart failure, approaches to blunt its influence on relaxation may be clinically useful.
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Is Delayed Relaxation an Important Determinant of Late-Diastolic Stiffness? |
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Despite recent progress in understanding determinants of myocardial relaxation, we still do not know whether this is an important contributor to late diastolic filling pressures. On the basis of a monoexponential decay model and normal time constant of 30 to 40 ms,59 one predicts pressure related to decaying LV contraction would be <2 mm Hg after
125 ms. Because diastole usually extends for an additional 250 ms, this would seem a minor issue. However, decay may not follow a single monoexponential course and can be influenced by superimposition of chamber filling (muscle re-extension) and the force applied at the time of refilling45,63 (eg, pressure at time of mitral valve opening).44 Tachycardia can shorten the available time for relaxation, and in hypertrophied ventricles, may be associated with elevated diastolic pressure.64 However, this has been shown to reflect atrial contraction force and timing of atrial systole rather than relaxation delay.65 Myocardial viscosity (even with full relaxation) can also underlie pressure rise at faster filling rates,66–68 and has been ascribed to microtubule levels69,70 and titin–actin interaction.67 Yet in normal hearts, viscosity is similar in both early versus late diastole, suggesting it is less likely to reflect ongoing active relaxation but more likely intrinsic strain–rate-dependent properties.68 The clinical settings in which relaxation delay might influence late-diastolic pressures most are tachycardia and afterload increase. In patients with cardiac failure symptoms but nondilated hearts and preserved ejection fraction, elevating arterial load can produce marked hypertension-delaying relaxation, and this has been associated with elevated EDP.59 However, in the animal studies, afterload had to be raised to 80% of maximum (100% being isovolumic contraction) to raise EDP,71 well above physiologic or even pathophysiologic loads. Clinical studies suggesting coupling of relaxation delay with EDP rise have generally not measured transmural LV pressure, thus failing to account for right ventricular (RV) and pericardial constraints, and have neglected neurohumoral activation. On the basis of available data, we believe it unlikely that relaxation delay has a major effect on late-diastolic pressures in most pathophysiologic settings and that relaxation delay and elevation of late-diastolic pressures are usually concurrent events.
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How Does Titin Influence Diastolic Chamber Compliance? |
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Over the normal operating range of sarcomeric length (<2.2 µm), a substantial component of diastolic muscle stiffness arises from proteins within the sarcomere itself. This was first shown in isolated myofibrils devoid of ion channels and extracellular matrix yet still comprised of the full complement of intrasarcomeric proteins.72 Most of this elastic force is now thought to reside in the macromolecule titin,73–75 whereas contributions of microtubules (tubulin) and intermediate filaments (desmin) appear <10% at operating sarcomere lengths.73 Titin is expressed as varying isoforms that impart different mechanical properties, and this likely plays a role in altering passive stiffness in failing hearts.75–77 Titin can also be post-translationally modified by Ca2+ (even in the diastolic range) and by phosphorylation,78,79 blurring notions of passive versus active tone.
The passive tension of titin is associated with an extensible region located at the I-band of sarcomeres, comprised of serially linked but distinct immunoglobulin and PEVK elements. It is expressed in 2 primary isoforms, a smaller N2B, which contains a shorter extensible segment in the I-band, and the larger more compliant N2BA isoform, which has longer segments and more immunoglobulin elements. Relative expression of these isoforms differs among species, with N2B predominating in rodents and greater N2BA observed in larger mammals.75 This, along with tandem changes in myocardial collagen across species, may determine species-dependent diastolic stiffening.75 Titin isoform shifting also appears during cardiac development, with a fetal isoform contributing to increased distensibility and declining in maturing heart.80 In tachypacing-induced heart failure dogs77 and in spontaneously hypertensive rats,81 elevation of diastolic muscle stiffness is accompanied by increased N2B expression (shorter, stiffer), whereas in a rat infarct model and in patients with end-stage ischemic (but maybe nonischemic) cardiomypathy, N2BA expression appears more prominent.76 In turn, the latter seems to correspond to reduced myocardial stiffness.
Although the correlation of titin isoform and muscle stiffness seems consistent among studies, the direction of isoform switching is not, and mechanisms that might lead to one type of shift over another in heart failure remain unclear. Differences among studies include technical processing of tissue, complexity of disease conditions including chronic pharmacological treatments, species differences, etc. Furthermore, correlations between isoform and function remain based on very limited data, particularly from human samples.
In addition to structural differences, post-translational modification of titin is likely an important mechanism for dynamic modulation of diastolic tension. Titin can be phosphorylated by PKA, and this acutely shifts the diastolic length tension relation downward (ie, enhanced compliance).79 Furthermore, diastolic tension is produced not only by titin extension but also by titin–actin interaction, and this can be inhibited in a calcium-dependent manner by S100A1, a calcium-binding protein abundantly present in the myocardium.82 Diastolic tension resulting from titin determines systolic tension by altering net calcium sensitivity of actomyosin interaction.48,55 Finally, titin-exerted diastolic force can impact stretch-activated potassium channels.55
As noted, titin isoforms and collagen content tend to vary in parallel among species, preserving relative stiffness contributions at lower sarcomere length (titin) and higher length (collagen).75 However, this relationship may not be maintained in pathological states or with pharmacological interventions that target fibrosis in particular. For example, in a hypertensive rat model, angiotensin II receptor blockade at a dose that did not affect blood pressure prevented myocardial fibrosis but allowed for hypertrophy development with normal myocardial stiffness constant. This suggested a primary role for fibrosis,83 yet prevention of titin isoform shifting could also have occurred. Given the generally coordinated expression of stiff titin isoforms with interstitial fibrosis, it seems prudent to rule out titin isoform switches before attributing changes in LV stiffness to changes in interstitial fibrosis.
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What Is the Impact of Altered Collagen/Fibrosis? |
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The myocardial collagen network is comprised of endomysial fibers that surround individual myocytes and capillaries and interconnect them via filamentous struts, perimysial fibers that interweave muscle bundles, and epimysial fibers, forming a matrix adjacent to epicardial and endocardial endothelium. Perimysial fibers are especially important for diastolic tension generation at high sarcomere lengths. When isolated rat left ventricles are subjected to high filling pressures (30 to 70 mm Hg), these coiled fibers straighten and effectively fix sarcomere length at 2.2 µm.84
Many studies have suggested the importance of myocardial fibrosis to diastolic dysfunction. For example, intra-arteriolar collagenase perfusion that reduces perimysial fibers by 70% results in a right shift of the diastolic LV PV relationship with increased sarcomere length.85 Digestion of purely endomysial fibers has the opposite effect.86,87 Recent studies have begun targeting signaling factors to fibrosis, including transforming growth factor-ß,88 the sodium–hydrogen exchanger,89 angiotensin II receptor–mediated signaling,90 and chymase,91 correlating changes in collagen/fibrosis to chamber stiffening. Other studies have degraded collagen in normal and pressure-load hypertrophied papillary muscles with plasmin92 or oxidized glutathione and hydroxyproline,93 and inhibited collagen cross-links with ß-aminopropionitrile.94 All studies report reduced chamber diastolic stiffness but with rather extreme modifications of collagen.
Given these data, a direct linkage between fibrosis and stiffness might seem well established, yet controversy exists. Quantitative assessment of fibrosis in various murine transgenic models, larger animal failure models, and even in humans, has not always found correlations between stiffness and collagen content. For example, clear-cut hemodynamic evidence of restriction to diastolic filling (ie, square-root sign) occurs with endomyocardial fibrosis of late-stage Loeffler disease but is absent in pressure-overload LV hypertrophy because of aortic stenosis or arterial hypertension. This has led some to conclude that the quality of collagen (specifically cross-linking and glycation) plays a key role in translating quantity into mechanical stiffness. In such studies, the relative ratio of insoluble (cross-linked) to soluble (cyanogen bromide digestion) collagen is most important. For example, in rats exposed to aortic banding, hypertrophy was accompanied by increased total collagen, yet fall in insoluble/soluble collagen ratio and no change in myocardial stiffness. In contrast, spontaneously hypertensive rats had elevated total collagen and higher insoluble/soluble collagen ratio, which correlated with chamber stiffening.95 In a model of accelerated diastolic dysfunction from angiotensin II stimulation and tachypacing, there were poor correlations between collagen deposition and stiffness but evidence that metalloproteinase activation may influence stiffness by alternative mechanisms.96 Finally, advanced glycation endproducts (AGEs) forming collagen cross-links may serve as a mechanism for cardiac stiffening because aged dogs fed a cross-link breaker had improved chamber compliance.97 In a volume overload model that did not alter total collagen, regional formation of AGE–collagen links correlated with stiffening.98 Thus, the importance of collagen amount versus post-translational structure remains a subject for debate. Both likely contribute, but the distinction is important because new strategies are under development to target fibrosis per se or to alter cross-link structures that may render even normal levels of collagen more distensible.
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Is There Active Diastolic Tone? |
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Beyond biophysical properties of structural proteins such as titin or collagen, diastolic stiffness is thought to be under active control as well. Cross-bridge interaction occurs even at low levels of diastolic calcium producing resting muscle tone. This was recently examined in a permeabilized canine multicellular myocardial preparation, in which sudden stretch led to an initial rapid nonlinear tension increase dependent on bath-solution Ca2+ and reversibly blocked by 5 mmol/L 2,3-butanedionemonoxime (a cross-bridge inhibitor).99 The threshold calcium was 630 nmol/L (higher than that thought present during diastole in normal working hearts), and this plus other technical issues (eg, use of room temperature) make it hard to translate these results to intact hearts. However, active tone attributable to calcium–myofilament interaction has the potential to explain some acute clinical episodes of heart failure such that occur during abrupt hypertension or episodes of demand angina. In feline pressure-hypertrophied cardiomyocytes, diastolic constitutive properties depend on intracellular calcium concentration.66 The link between cardiomyocyte diastolic constitutive properties and intracellular calcium could be low-grade diastolic cross-bridge cycling, previously shown to coincide with small diastolic cytosolic calcium sparks.100 In failing hearts, sarcoplasmic reticular calcium leak and potentially enhanced reverse mode current via the NCX may elevate diastolic calcium so that such tone would be more relevant. Elevation of beat frequency in the presence of depressed sarcoplasmic reticular calcium uptake can raise diastolic calcium, although this appears to be less than initially reported,101 and effects on human diastolic pressures are also modest.102
Modifications of myofilament–calcium sensitivity by heart failure could also alter active tone. This includes changes associated with PKA (or phosphoglycerate kinase [PKG]) phosphorylation of myosin light chain 2 and TnI,61 the latter also likely underlying NO modulation because NO and cGMP increase resting diastolic cell length as a result of PKG-mediated phosphorylation of myofilaments.103,104 In intact hearts, the diastolic PV trajectory during filling is displaced downward in patients with dilated cardiomyopathy administered intracoronary substance P (NO-stimulator),105,106 whereas 10 days of NO synthase blockade with NG-monomethyl-L-arginine in conscious dogs results in the opposite change,107 even accounting for external load effects.
Diastolic distensibility may also be influenced by myocardial energetics. Hypoxia increases isovolumic resting tension in isolated guinea pig hearts108 and raises the diastolic PV curve in humans during balloon coronary angioplasty.109 Reductions in LV diastolic distensibility have also been observed during demand ischemia.110,111 In this setting, the idea of reduced diastolic LV distensibility caused by Ca2+ overload was recently rebutted by experiments in blood-perfused isovolumic rabbit hearts that demonstrated correction of the ischemia-induced decline in LV diastolic distensibility by quick stretches, which disrupted rigor bounds, and not by a calcium desensitizer (2,3-butanedionemonoxime).112 Change in high-energy phosphate metabolism may also contribute. For example, inhibition of creatine kinase activity by low-dose iodoacetamide resulted in an increase in free [MgADP] without alterations in [MgATP], [Pi], or [pHi], and in intact hearts, resulted in a 3x increase in ventricular EDP and delayed relaxation.113 The LVEDP increase correlated with free ADP. This was further supported by data in isolated hypertrophied rat hearts, in which fairly selective increased free [ADP] correlated with increased LVEDP.114 In vitro motility assays support slowing of cross-bridge detachment by free MgADP115,116 because of competition with MgATP for the substrate site on myosin,117 and this binding appears dependent on myosin light chain 2.118 Unfortunately, there have been no previous reported in vivo studies (clinical or experimental) in which modulation of free [ADP] has been definitively linked to changes in chamber distensibility.
Many pharmacological agents modify myocellular [Ca2+]i or Ca2+ sensitivity, yet repeatedly, such interventions often leave the diastolic PV relation in intact normal heart unaltered, and similar findings have been reported in hypertrophied119 and failing hearts120,121 when assessed by comprehensive PV relations. The contribution of diastolic tone to basal diastolic LV properties is therefore probably small but this does not exclude a potential role in acute and reversible clinical settings such as hypertensive pulmonary edema or demand angina. Modulation of factors influencing active tone may have an impact in these settings and warrant further investigation.
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What Is the Role of Extrinsic Forces? |
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The slope of the passive diastolic PV relation (DPVR) ideally using transmural pressure describes the intrinsic stiffness of the ventricle. The primary indication of altered stiffness is a change in the local slope of this relation at a matched preload. However, many if not most interventions studied in vivo displace the PV trajectory during diastolic filling upward or downward with minimal change in shape. In part, this is attributable to the use of chamber pressure (not transmural pressure) and thus impact of external loading conditions and intrathoracic pressure. There are many examples of this, such as acute elevation during exercise or acute coronary occlusion,122 or downward shifts after administration of calcium channel blockers,123,124 angiotensin-converting enzyme (ACE) inhibitors, or sodium nitroprusside. The key question is whether this reflects changes in myocardial stiffness or is largely the result of changes in external constraining forces from the pericardium or right heart. Although relevant studies span a period of >2 decades, this question remains a subject of debate.
Several methods have been used to index the influence of external forces on the diastolic PV trajectory. One is to acutely remove the pericardium, which has been useful to quantify these forces,125 and rule out its influence on stiffening from rapid-pacing–induced ischemia.126,127 Another approach more easily translated to humans is deriving the passive DPVR from multiple cardiac cycles, using only late-diastolic data measured after unloading of the right heart by inferior vena caval obstruction.123,128 Here, right heart pressures fall before a decline in LV filling (the decline itself indexes constraint), and the DPVR is then assessed more independent of these forces.128 On the basis of this approach, between 30% and 40% of the resting late-diastolic pressures in humans appear ascribable to external loads. Vertical shifts in the diastolic PV trajectory from resting beats are often minimized when the DVPR is assessed in this manner,123 raising doubts about the presence of true intrinsic stiffness changes. Demand ischemia may be different in this regard,129 although protocols using RV unloading have not been performed. Finally, pharmacological agents can be infused intracoronary to minimize the impact of external loading, although once drained from the coronary sinus, they pass into the venous and arterial systemic circulations, so this influence is blunted but not eliminated. Still, this method has suggested that pharmacological agents such as ACE inhibitors may acutely improve chamber distensibility in both failing130 and hypertrophied hearts.131
Some cardiac disorders display marked disparities between the intact (loaded) DPVR and that measured from multiple cycles with RV unloading. For example, in patients with hypertrophic cardiomyopathy and septal hypertrophy, baseline DPVRs are very flat, although shifted upward at higher pressures.132 DPVRs derived by the latter method are much steeper and follow a completely different relation. The mechanism for such striking disparities remains conjectural. Altered septal geometry with a concatenoid-shaped septum may accentuate ventricular interaction, and filling purely by shape, change after cavity obliteration may allow volumes to rise without stretching sarcomeres. The downward displacement observed with simple reduction of preload in such hearts raises caution when interpreting similar DPVR shifts from vasoactive agents such as calcium channel blockers. DPVRs from human ventricles in isolation have not been studied, and unfortunately, genetically engineered models of hypertrophic disease in rodents41 have not as yet recapitulated diastolic compliance changes observed in human hypertrophic cardiomyopathy. For that matter, and for all their attractive features, small rodent models have generally not been very useful for studying the pathophysiology of diastolic compliance abnormalities because this seems only achieved in these species when there is profound extensive fibrosis or structural changes.
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Is There Such a Thing as Diastolic Heart Failure? |
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Many patients present with symptoms of cardiac failure, including exertional dyspnea, fluid retention, and pulmonary edema, yet have apparent preservation of systolic function. Epidemiologic studies indicate the prevalence of this form of failure is very high among community-based populations, accounting for nearly half of all patients with congestive heart failure.1,133,134 Patients are more often elderly, female, hypertensive, and have ventricular hypertrophy,135 and their symptoms, neurohumoral activation (risk for poor outcome), and overall morbidity and mortality appear similar to those with depressed systolic function. The syndrome has been presumptively termed diastolic heart failure, yet this assumes systolic function is indeed normal, that diastolic abnormalities are present and a primary mechanism for disease, and that comorbidities such as chronic lung disease, ischemia, and metabolic disorders play a minor role. Each of these assumptions has been recently brought into question.136,137 Because there are few experimental models for this syndrome and none that truly recapitulate its primary clinical features, most current understanding stems from patient studies.
Diastolic dysfunction is indeed common because most patients have elevated EDP or delayed relaxation, many with normal or reduced diastolic chamber volumes (ie, lower compliance).138 However, accurate analysis of chamber volume on the basis of 3D imaging methods such as MRI or echocardiography remains scant. The majority of data are based on noninvasive parameters that indirectly index diastolic properties often determined under stable resting conditions. Furthermore, many of these indexes are abnormal in elderly hypertensive individuals without symptoms of cardiac failure.139 Invasive data are also based primarily on rest conditions so changes resulting from loading that might have been altered during decompensation are generally missed. Acute valvular insufficiency and systolic depression do not appear to be a feature of such decompensations,140 yet how diastolic dysfunction at rest often in the absence of symptoms is responsible for such decompensation remains unclear.
Recent evidence from a small but well-studied cohort suggests that additional abnormalities may contribute, including ventricular systolic and arterial stiffening.59 The latter can be more easily linked to arterial blood pressure and symptom lability and diuretic sensitivity, all common in affected patients. In this regard, this disorder may not be a disease of diastole per se, but rather reflect adverse interactions of vascular and ventricular stiffnesses affecting filling and ejection. This is more than an academic distinction because it refocuses attention on pathophysiology and helps target therapies. Diastolic dysfunction is likely a component of the disorder but not the sole target for ameliorating symptoms if other cardiovascular changes are similarly or even more important. Equally lacking are information as to myocardial substrate (very little biopsy or necropsy material has been studied) and genetic and proteomic profiling that might characterize diastolic dysfunction and eventually predict who is likely to develop the disease.
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Conclusion |
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TopAbstractIntroductionHow Do Myocytes Control...How Does Cardiac Load...Is Delayed Relaxation an...How Does Titin Influence...What Is the Impact...Is There Active Diastolic...What Is the Role...Is There Such a...ConclusionReferences |
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Although much is known about the mechanisms underlying diastolic dysfunction in heart failure, many basic issues remain to be resolved. As depicted in the Figure, clinically relevant diastolic dysfunction integrates abnormalities emanating from sarcomere, extracellular coupling apparatus, myocardial matrix, and cardiac structure and coupling with the vascular system. Much more work is still needed to clarify which are the most meaningful abnormalities that would best serve as primary clinical targets for therapeutic intervention. Models in which diastole is specifically manipulated would greatly help to test its role and to clarify the influences of genetic and post-translational modifications of key proteins. We need to build a more critical and accurate bridge between the findings obtained in reductionist models and the behavior that manifests in intact chambers. At the clinical end of the spectrum, we should focus less on descriptive behaviors and assigning guilt to diastolic abnormalities simply by their presence and more on proof of pathophysiologic relevance and on integrating diastolic findings with coexisting cardiovascular abnormalities. Given our new and powerful tools, answers to these questions are undoubtedly on the way.
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Acknowledgments |
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This study was supported by National Institute of Health grants AG18324, HL47511, and HL52307 (D.A.K.).
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Footnotes |
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Original received January 21, 2004; revision received April 12, 2004; accepted April 13, 2004.
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References |
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TopAbstractIntroductionHow Do Myocytes Control...How Does Cardiac Load...Is Delayed Relaxation an...How Does Titin Influence...What Is the Impact...Is There Active Diastolic...What Is the Role...Is There Such a...ConclusionReferences |
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1. Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, Marburger CT, Brosnihan B, Morgan TM, Stewart KP. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002; 288: 2144–2150.
2. 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: 1387–1393.
3. Ommen SR, Nishimura RA. A clinical approach to the assessment of left ventricular diastolic function by Doppler echocardiography: update 2003. Heart. 2003; 89 (suppl 3): iii18–iii23.
4. Naqvi TZ. Diastolic function assessment incorporating new techniques in Doppler echocardiography. Rev Cardiovasc Med. 2003; 4: 81–99.[Medline] [Order article via Infotrieve]
5. Hoit BD. Spectral and color M-mode Doppler in genetically altered mice. Assessment of diastolic function. Minerva Cardioangiol. 2000; 51: 609–618.
6. Frank KF, Bolck B, Brixius K, Kranias EG, Schwinger RH. Modulation of SERCA: implications for the failing human heart. Basic Res Cardiol. 2002; 97 (suppl 1): I72–I78.[Medline] [Order article via Infotrieve]
7. del Monte F, Harding SE, Dec GW, Gwathmey JK, Hajjar RJ. Targeting phospholamban by gene transfer in human heart failure. Circulation. 2002; 105: 904–907.
8. MacLennan DH, Kranias EG. Phospholamban: a crucial regulator of cardiac contractility. Nat Rev Mol Cell Biol. 2003; 4: 566–577.[CrossRef][Medline] [Order article via Infotrieve]
9. Hasenfuss G, Pieske B. Calcium cycling in congestive heart failure. J Mol Cell Cardiol. 2002; 34: 951–969.[CrossRef][Medline] [Order article via Infotrieve]
10. O’Rourke B, Kass DA, Tomaselli GF, Kaab S, Tunin R, Marban E. Mechanisms of altered excitation-contraction coupling in canine tachycardia-induced heart failure, I: experimental studies. Circ Res. 1999; 84: 562–570.
11. Schwinger RH, Munch G, Bolck B, Karczewski P, Krause EG, Erdmann E. Reduced Ca(2+)-sensitivity of SERCA 2a in failing human myocardium due to reduced serin-16 phospholamban phosphorylation. J Mol Cell Cardiol. 1999; 31: 479–491.[CrossRef][Medline] [Order article via Infotrieve]
12. Neumann J. Altered phosphatase activity in heart failure, influence on Ca2+ movement. Basic Res Cardiol. 2002; 97 (suppl 1): I91–I95.[Medline] [Order article via Infotrieve]
13. Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ, DePaoli-Roach AA, Kranias EG. Type 1 phosphatase, a negative regulator of cardiac function. Mol Cell Biol. 2002; 22: 4124–4135.
14. Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Bodi I, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD. PKC-alpha regulates cardiac contractility and propensity toward heart failure. Nat Med. 2004; 10: 248–254.[CrossRef][Medline] [Order article via Infotrieve]
15. MacLennan DH, Green NM. Structural biology. Pumping ions. Nature. 2000; 405: 633–634.[CrossRef][Medline] [Order article via Infotrieve]
16. Toyoshima C, Asahi M, Sugita Y, Khanna R, Tsuda T, MacLennan DH. Modeling of the inhibitory interaction of phospholamban with the Ca2+ ATPase. Proc Natl Acad Sci U S A. 2003; 100: 467–472.
17. Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T, Guerrero JL, Gwathmey JK, Rosenzweig A, Hajjar RJ. Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci U S A. 2000; 97: 793–798.
18. del Monte F, Hajjar RJ. Targeting calcium cycling proteins in heart failure through gene transfer. J Physiol. 2003; 546: 49–61.
19. Hoshijima M, Ikeda Y, Iwanaga Y, Minamisawa S, Date MO, Gu Y, Iwatate M, Li M, Wang L, Wilson JM, Wang Y, Ross J Jr, Chien KR. Chronic suppression of heart-failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nat Med. 2002; 8: 864–871.[Medline] [Order article via Infotrieve]
20. Luo W, Grupp IL, Harrer J, Ponniah S, Grupp G, Duffy JJ, Doetschman T, Kranias EV. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of ß-agonist stimulation. Circ Res. 1994; 75: 401–409.
21. Champion HC, Georgakopoulos D, Haldar S, Wang L, Wang Y, Kass DA. Robust adenoviral and adeno-associated viral gene transfer to the in vivo murine heart: application to study of phospholamban physiology. Circulation. 2003; 108: 2790–2797.
22. Marks AR, Reiken S, Marx SO. Progression of heart failure: is protein kinase a hyperphosphorylation of the ryanodine receptor a contributing factor? Circulation. 2002; 105: 272–275.
23. Reiken S, Gaburjakova M, Guatimosim S, Gomez AM, D’Armiento J, Burkhoff D, Wang J, Vassort G, Lederer WJ, Marks AR. Protein kinase A phosphorylation of the cardiac calcium release channel (ryanodine receptor) in normal and failing hearts. Role of phosphatases and response to isoproterenol. J Biol Chem. 2003; 278: 444–453.
24. Reiken S, Wehrens XH, Vest JA, Barbone A, Klotz S, Mancini D, Burkhoff D, Marks AR. Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation. 2003; 107: 2459–2466.
25. Doi M, Yano M, Kobayashi S, Kohno M, Tokuhisa T, Okuda S, Suetsugu M, Hisamatsu Y, Ohkusa T, Kohno M, Matsuzaki M. Propranolol prevents the development of heart failure by restoring FKBP12.6-mediated stabilization of ryanodine receptor. Circulation. 2002; 105: 1374–1379.
26. Ginsburg KS, Bers DM. Modulation of excitation-contraction coupling by isoproterenol in cardiomyocytes with controlled SR Ca load and ICa trigger. J Physiol. 2004.
27. Li Y, Kranias EG, Mignery GA, Bers DM. Protein kinase A phosphorylation of the ryanodine receptor does not affect calcium sparks in mouse ventricular myocytes. Circ Res. 2002; 90: 309–316.
28. Armoundas AA, Hobai IA, Tomaselli GF, Winslow RL, O’Rourke B. Role of sodium-calcium exchanger in modulating the action potential of ventricular myocytes from normal and failing hearts. Circ Res. 2003; 93: 46–53.
29. Hasenfuss G, Schillinger W, Lehnart SE, Preuss M, Pieske B, Maier LS, Prestle J, Minami K, Just H. Relationship between Na+-Ca2+-exchanger protein levels and diastolic function of failing human myocardium. Circulation. 1999; 99: 641–648.
30. Weisser-Thomas J, Piacentino V III, Gaughan JP, Margulies K, Houser SR. Calcium entry via Na/Ca exchange during the action potential directly contributes to contraction of failing human ventricular myocytes. Cardiovasc Res. 2003; 57: 974–985.
31. Weber CR, Piacentino V III, Houser SR, Bers DM. Dynamic regulation of sodium/calcium exchange function in human heart failure. Circulation. 2003; 108: 2224–2229.
32. Westfall MV, Borton AR, Albayya FP, Metzger JM. Myofilament calcium sensitivity and cardiac disease: insights from troponin I isoforms and mutants. Circ Res. 2002; 91: 525–531.
33. Wolska BM, Vijayan K, Arteaga GM, Konhilas JP, Phillips RM, Kim R, Naya T, Leiden JM, Martin AF, de Tombe PP, Solaro RJ. Expression of slow skeletal troponin I in adult transgenic mouse heart muscle reduces the force decline observed during acidic conditions. J Physiol. 2001; 536: 863–870.
34. Takimoto E, Soergel DG, Janssen PM, Stull LB, Kass DA, Murphy AM. Frequency- and afterload-dependent cardiac modulation in vivo by troponin I with constitutively active protein kinase A phosphorylation sites. Circ Res. 2004; 94: 496–504.
35. Palmer S, Di Bello S, Herzig JW. The effects of EMD 57033 on rigor tension in porcine skinned cardiac trabecula. Eur J Pharmacol. 1995; 294: 83–90.[CrossRef][Medline] [Order article via Infotrieve]
36. Solaro RJ, Gambassi G, Warshaw DM, Keller MR, Spurgeon HA, Beier N, Lakatta EG. Stereoselective actions of thiadiazinones on canine cardiac myocytes and myofilaments. Circ Res. 1993; 73: 981–990.
37. Hajjar RJ, Schmidt U, Helm P, Gwathmey JK. Ca++ sensitizers impair cardiac relaxation in failing human myocardium. J Pharmacol Exp Ther. 1997; 280: 247–254.
38. Perez NG, Gao WD, Marban E. Novel myofilament Ca2+-sensitizing property of xanthine oxidase inhibitors. Circ Res. 1998; 83: 423–430.
39. Ekelund UE, Harrison RW, Shokek O, Thakkar RN, Tunin RS, Senzaki H, Kass DA, Marban E, Hare JM. Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure. Circ Res. 1999; 85: 437–445.
40. Fitzsimons DP, Patel JR, Moss RL. Role of myosin heavy chain composition in kinetics of force development and relaxation in rat myocardium. J Physiol. 1998; 513: 171–183.
41. Georgakopoulos D, Christe ME, Giewat M, Seidman CM, Seidman JG, Kass DA. The pathogenesis of familial hypertrophic cardiomyopathy: early and evolving effects from an alpha-cardiac myosin heavy chain missense mutation. Nat Med. 1999; 5: 327–330.[CrossRef][Medline] [Order article via Infotrieve]
42. Geisterfer-Lowrance AA, Christe M, Conner DA, Ingwall JS, Schoen FJ, Seidman CE, Seidman JG. A mouse model of familial hypertrophic cardiomyopathy. Science. 1996; 272: 731–734.[Abstract]
43. Yellin EL, Hori M, Yoran C, Sonnenblick EH, Gabbay S, Frater RWM. Left ventricular relaxation in the filling and nonfilling intact canine heart. Am J Physiol. 1986; 250: H620–H629.[Medline] [Order article via Infotrieve]
44. Nikolic S, Yellin EL, Tamura K, Vetter H, Tamura T, Meisner JS, Frater RW. Passive properties of canine left ventricle: diastolic stiffness and restoring forces. Circ Res. 1988; 62: 1210–1222.
45. Paulus WJ, Vantrimpont PJ, Rousseau MF. Diastolic function of the nonfilling human left ventricle. J Am Coll Cardiol. 1992; 20: 1524–1532.[Abstract]
46. Bell SP, Nyland L, Tischler MD, McNabb M, Granzier H, LeWinter MM. Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res. 2000; 87: 235–240.
47. Helmes M, Lim CC, Liao R, Bharti A, Cui L, Sawyer DB. Titin determines the Frank-Starling relation in early diastole. J Gen Physiol. 2003; 121: 97–110.
48. Fukuda N, Sasaki D, Ishiwata S, Kurihara S. Length dependence of tension generation in rat skinned cardiac muscle: role of titin in the Frank-Starling mechanism of the heart. Circulation. 2001; 104: 1639–1645.
49. Senzaki H, Fetics B, Chen CH, Kass DA. Comparison of ventricular pressure relaxation assessments in human heart failure: quantitative influence on load and drug sensitivity analysis. J Am Coll Cardiol. 1999; 34: 1529–1536.
50. Matsubara H, Takaki M, Yasuhara S, Araki J, Suga H. Logistic time constant of isovolumic relaxation pressure-time curve in the canine left ventricle. Better alternative to exponential time constant. Circulation. 1995; 92: 2318–2326.
51. Zile MR, Gaasch WH. Mechanical loads and the isovolumic and filling indices of left ventricular relaxation. Prog Cardiovasc Dis. 1990; 32: 333–346.[CrossRef][Medline] [Order article via Infotrieve]
52. Paulus WJ, Bronzwaer JG, Felice H, Kishan N, Wellens F. Deficient acceleration of left ventricular relaxation during exercise after heart transplantation. Circulation. 1992; 86: 1175–1185.
53. Vantrimpont PJ, Felice H, Paulus WJ. Does dobutamine prevent the rise in left ventricular filling pressures observed during exercise after heart transplantation? Eur Heart J. 1995; 16: 1300–1306.
54. Coudray N, Beregi JP, Lecarpentier Y, Chemla D. Effects of isoproterenol on myocardial relaxation rate: influence of the level of load. Am J Physiol. 1993; 265: H1645–H1653.[Medline] [Order article via Infotrieve]
55. Granzier H, Labeit S. Cardiac titin: an adjustable multi-functional spring. J Physiol. 2002; 541: 335–342.
56. Gillebert TC, Leite-Moreira AF, De Hert SG. Load dependent diastolic dysfunction in heart failure. Heart Fail Rev. 2000; 5: 345–355.[CrossRef][Medline] [Order article via Infotrieve]
57. Leite-Moreira AF, Correia-Pinto J, Gillebert TC. Afterload induced changes in myocardial relaxation: a mechanism for diastolic dysfunction. Cardiovasc Res. 1999; 43: 344–353.
58. Hori M, Inoue M, Kitakaze M, Tsujioka K, Ishida Y, Fukunami M, Nakajima S, Kitabatake A, Abe H. Loading sequence is a major determinant of afterload-dependent relaxation in intact canine heart. Am J Physiol. 1985; 249: H747–H754.[Medline] [Order article via Infotrieve]
59. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations. Circulation. 2003; 107: 714–720.
60. Paulus WJ, Heyndrickx GR, Buyl P, Goethals MA, Andries E. Wide-range load shift of combined aortic valvuloplasty-arterial vasodilation slows isovolumic relaxation of the hypertrophied left ventricle. Circulation. 1990; 81: 886–898.
61. Van der Venden, V, Papp Z, Zaremba R, Boontje NM, de Jong JW, Owen VJ, Burton PB, Goldmann P, Jaquet K, Stienen GJ. Increased Ca2+-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins. Cardiovasc Res. 2003; 57: 37–47.
62. Bodor GS, Oakeley AE, Allen PD, Crimmins DL, Ladenson JH, Anderson PA. Troponin I phosphorylation in the normal and failing adult human heart. Circulation. 1997; 96: 1495–1500.
63. Sys SU, Paulus WJ, Claes VA, Brutsaert DL. Post-reextension force decay of relaxing cardiac muscle. Am J Physiol. 1987; 253: H256–H261.[Medline] [Order article via Infotrieve]
64. Gelpi RJ, Pasipoularides A, Lader AS, Patrick TA, Chase N, Hittinger L, Shannon RP, Bishop SP, Vatner SF. Changes in diastolic cardiac function in developing and stable perinephritic hypertension in conscious dogs. Circ Res. 1991; 68: 555–567.
65. Berger RD, Wolff MR, Anderson JH, Kass DA. Role of atrial contraction in diastolic pressure elevation induced by rapid pacing of hypertrophied canine ventricle. Circ Res. 1995; 77: 163–173.
66. Zile MR, Richardson K, Cowles MK, Buckley JM, Koide M, Cowles BA, Gharpuray V, Cooper G. Constitutive properties of adult mammalian cardiac muscle cells. Circulation. 1998; 98: 567–579.
67. Kulke M, Fujita-Becker S, Rostkova E, Neagoe C, Labeit D, Manstein DJ, Gautel M, Linke WA. Interaction between PEVK-titin and actin filaments: origin of a viscous force component in cardiac myofibrils. Circ Res. 2001; 89: 874–881.
68. Fraites TJ Jr, Saeki A, Kass DA. Effect of altering filling pattern on diastolic pressure-volume curve. Circulation. 1997; 96: 4408–4414.
69. Tsutsui H, Ishihara K, Cooper G. Cytoskeletal role in the contractile dysfunction of hypertrophied myocardium. Science. 1993; 260: 682–687.
70. Koide M, Hamawaki M, Narishige T, Sato H, Nemoto S, DeFreyte G, Zile MR, Cooper G, IV, Carabello BA. Microtubule depolymerization normalizes in vivo myocardial contractile function in dogs with pressure-overload left ventricular hypertrophy. Circulation. 2000; 102: 1045–1052.
71. Leite-Moreira AF, Correia-Pinto J. Load as an acute determinant of end-diastolic pressure-volume relation. Am J Physiol Heart Circ Physiol. 2001; 280: H51–H59.
72. Linke WA, Popov VI, Pollack GH. Passive and active tension in single cardiac myofibrils. Biophys J. 1994; 67: 782–792.[Medline] [Order article via Infotrieve]
73. Granzier HL, Irving TC. Passive tension in cardiac muscle: contribution of collagen, titin, microtubules, and intermediate filaments. Biophys J. 1995; 68: 1027–1044.[Medline] [Order article via Infotrieve]
74. Linke WA, Fernandez JM. Cardiac titin: molecular basis of elasticity and cellular contribution to elastic and viscous stiffness components in myocardium. J Muscle Res Cell Motil. 2002; 23: 483–497.[CrossRef][Medline] [Order article via Infotrieve]
75. Wu Y, Cazorla O, Labeit D, Labeit S, Granzier H. Changes in titin and collagen underlie diastolic stiffness diversity of cardiac muscle. J Mol Cell Cardiol. 2000; 32: 2151–2162.[CrossRef][Medline] [Order article via Infotrieve]
76. Neagoe C, Kulke M, del Monte F, Gwathmey JK, de Tombe PP, Hajjar RJ, Linke WA. Titin isoform switch in ischemic human heart disease. Circulation. 2002; 106: 1333–1341.
77. Wu Y, Bell SP, Trombitas K, Witt CC, Labeit S, LeWinter MM, Granzier H. Changes in titin isoform expression in pacing-induced cardiac failure give rise to increased passive muscle stiffness. Circulation. 2002; 106: 1384–1389.
78. Labeit D, Watanabe K, Witt C, Fujita H, Wu Y, Lahmers S, Funck T, Labeit S, Granzier H. Calcium-dependent molecular spring elements in the giant protein titin. Proc Natl Acad Sci U S A. 2003; 100: 13716–13721.
79. Yamasaki R, Wu Y, McNabb M, Greaser M, Labeit S, Granzier H. Protein kinase A phosphorylates titin’s cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. Circ Res. 2002; 90: 1181–1188.
80. Lahmers S, Wu Y, Call DR, Labeit S, Granzier H. Developmental control of titin isoform expression and passive stiffness in fetal and neonatal myocardium. Circ Res. 2004; 94: 505–513.
81. Warren CM, Jordan MC, Roos KP, Krzesinski PR, Greaser ML. Titin isoform expression in normal and hypertensive myocardium. Cardiovasc Res. 2003; 59: 86–94.
82. Yamasaki R, Berri M, Wu Y, Trombitas K, McNabb M, Kellermayer MS, Witt C, Labeit D, Labeit S, Greaser M, Granzier H. Titin-actin interaction in mouse myocardium: passive tension modulation and its regulation by calcium/S100A1. Biophys J. 2001; 81: 2297–2313.[Medline] [Order article via Infotrieve]
83. Yamamoto K, Masuyama T, Sakata Y, Nishikawa N, Mano T, Yoshida J, Miwa T, Sugawara M, Yamaguchi Y, Ookawara T, Suzuki K, Hori M. Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart. Cardiovasc Res. 2002; 55: 76–82.
84. Factor SM, Flomenbaum M, Zhao MJ, Eng C, Robinson TF. The effects of acutely increased ventricular cavity pressure on intrinsic myocardial connective tissue. J Am Coll Cardiol. 1988; 12: 1582–1589.[Abstract]
85. MacKenna DA, Omens JH, McCulloch AD, Covell JW. Contribution of collagen matrix to passive left ventricular mechanics in isolated rat hearts. Am J Physiol. 1994; 266: H1007–H1018.[Medline] [Order article via Infotrieve]
86. Lamberts RR, Willemsen MJ, Perez NG, Sipkema P, Westerhof N. Acute and specific collagen type I degradation increases diastolic and developed tension in perfused rat papillary muscle. Am J Physiol Heart Circ Physiol. 2003.
87. Todaka K, Jiang T, Chapman JT, Gu A, Zhu SM, Herzog E, Hochman JS, Steinberg SF, Burkhoff D. Functional consequences of acute collagen degradation studied in crystalloid perfused rat hearts. Basic Res Cardiol. 1997; 92: 147–158.[CrossRef][Medline] [Order article via Infotrieve]
88. Kuwahara F, Kai H, Tokuda K, Kai M, Takeshita A, Egashira K, Imaizumi T. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation. 2002; 106: 130–135.
89. Ennis IL, Escudero EM, Console GM, Camihort G, Dumm CG, Seidler RW, Camilion de Hurtado MC, Cingolani HE. Regression of isoproterenol-induced cardiac hypertrophy by Na+/H+ exchanger inhibition. Hypertension. 2003; 41: 1324–1329.
90. Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL. Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation. 2002; 105: 2512–2517.
91. Matsumoto T, Wada A, Tsutamoto T, Ohnishi M, Isono T, Kinoshita M. Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. Circulation. 2003; 107: 2555–2558.
92. Stroud JD, Baicu CF, Barnes MA, Spinale FG, Zile MR. Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment. Am J Physiol Heart Circ Physiol. 2002; 282: H2324–H2335.
93. Brower GL, Janicki JS. Contribution of ventricular remodeling to pathogenesis of heart failure in rats. Am J Physiol Heart Circ Physiol. 2001; 280: H674–H683.
94. Kato S, Spinale FG, Tanaka R, Johnson W, Cooper G, Zile MR. Inhibition of collagen cross-linking: effects on fibrillar collagen and ventricular diastolic function. Am J Physiol. 1995; 269: H863–H868.[Medline] [Order article via Infotrieve]
95. Badenhorst D, Maseko M, Tsotetsi OJ, Naidoo A, Brooksbank R, Norton GR, Woodiwiss AJ. Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodeling in hypertension in rats. Cardiovasc Res. 2003; 57: 632–641.
96. Senzaki H, Paolocci N, Gluzband YA, Lindsey ML, Janicki JS, Crow MT, Kass DA. Beta-blockade prevents sustained metalloproteinase activation and diastolic stiffening induced by angiotensin II combined with evolving cardiac dysfunction. Circ Res. 2000; 86: 807–815.
97. Asif M, Egan J, Vasan S, Jyothirmayi GN, Masurekar MR, Lopez S, Williams C, Torres RL, Wagle D, Ulrich P, Cerami A, Brines M, Regan TJ. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci U S A. 2000; 97: 2809–2813.
98. Herrmann KL, McCulloch AD, Omens JH. Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy. Am J Physiol Heart Circ Physiol. 2003; 284: H1277–H1284.
99. Campbell KS, Patel JR, Moss RL. Cycling cross-bridges increase myocardial stiffness at submaximal levels of Ca2+ activation. Biophys J. 2003; 84: 3807–3815.[Medline] [Order article via Infotrieve]
100. Lakatta EG, Lappe DL. Diastolic scattered light fluctuation, resting force and twitch force in mammalian cardiac muscle. J Physiol. 1981; 315: 369–394.
101. Mulieri LA, Hasenfuss G, Leavitt B, Allen PD, Alpert NR. Altered myocardial force-frequency relation in human heart failure. Circulation. 1992; 85: 1743–1750.
102. Liu CP, Ting CT, Lawrence W, Maughan WL, Chang MS, Kass DA. Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants. Circulation. 1993; 88: 1893–1906.
103. Shah AM, Spurgeon HA, Sollott SJ, Talo A, Lakatta EG. 8-bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. Circ Res. 1994; 74: 970–978.
104. Ito N, Bartunek J, Spitzer KW, Lorell BH. Effects of the nitric oxide donor sodium nitroprusside on intracellular pH and contraction in hypertrophied myocytes. Circulation. 1997; 95: 2303–2311.
105. Heymes C, Vanderheyden M, Bronzwaer JG, Shah AM, Paulus WJ. Endomyocardial nitric oxide synthase and left ventricular preload reserve in dilated cardiomyopathy. Circulation. 1999; 99: 3009–3016.
106. Bronzwaer JG, Zeitz C, Visser CA, Paulus WJ. Endomyocardial nitric oxide synthase and the hemodynamic phenotypes of human dilated cardiomyopathy and of athlete’s heart. Cardiovasc Res. 2002; 55: 270–278.
107. Post H, d’Agostino C, Lionetti V, Castellari M, Kang EY, Altarejos M, Xu X, Hintze TH, Recchia FA. Reduced left ventricular compliance and mechanical efficiency after prolonged inhibition of NO synthesis in conscious dogs. J Physiol. 2003; 552: 233–239.
108. Nayler WG, Yepez CE, Poole-Wilson PA. The effect of beta-adrenoceptor and Ca2+ antagonist drugs on the hypoxia-induced increased in resting tension. Cardiovasc Res. 1978; 12: 666–674.[Medline] [Order article via Infotrieve]
109. De Bruyne B, Bronzwaer JG, Heyndrickx GR, Paulus WJ. Comparative effects of ischemia and hypoxemia on left ventricular systolic and diastolic function in humans. Circulation. 1993; 88: 461–471.
110. Isoyama S, Apstein CS, Wexler LF, Grice WN, Lorell BH. Acute decrease in left ventricular diastolic chamber distensibility during simulated angina in isolated hearts. Circ Res. 1987; 61: 925–933.
111. Barry WH, Brooker JZ, Alderman EL, Harrison DC. Changes in diastolic stiffness and tone of the left ventricle during angina pectoris. Circulation. 1974; 49: 255–262.
112. Varma N, Morgan JP, Apstein CS. Mechanisms underlying ischemic diastolic dysfunction: relation between rigor, calcium homeostasis, and relaxation rate. Am J Physiol Heart Circ Physiol. 2003; 284: H758–H771.
113. Tian R, Christe ME, Spindler M, Hopkins JC, Halow JM, Camacho SA, Ingwall JS. Role of MgADP in the development of diastolic dysfunction in the intact beating rat heart. J Clin Invest. 1997; 99: 745–751.[Medline] [Order article via Infotrieve]
114. Tian R, Nascimben L, Ingwall JS, Lorell BH. Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation. 1997; 96: 1313–1319.
115. Metzger JM. Effects of phosphate and ADP on shortening velocity during maximal and submaximal calcium activation of the thin filament in skeletal muscle fibers. Biophys J. 1996; 70: 409–417.[Medline] [Order article via Infotrieve]
116. Lu Z, Swartz DR, Metzger JM, Moss RL, Walker JW. Regulation of force development studied by photolysis of caged ADP in rabbit skinned psoas fibers. Biophys J. 2001; 81: 334–344.[Medline] [Order article via Infotrieve]
117. Yamashita H, Sata M, Sugiura S, Momomura S, Serizawa T, Iizuka M. ADP inhibits the sliding velocity of fluorescent actin filaments on cardiac and skeletal myosins. Circ Res. 1994; 74: 1027–1033.
118. Fujita H, Sasaki D, Fukuda K, Ishiwata S. Myosin light chain 2 modulates MgADP-induced contraction in rabbit skeletal and bovine cardiac skinned muscle. J Physiol. 2002; 542: 221–229.
119. Kass DA, Wolff MR, Ting CT, Liu CP, Chang MS, Lawrence W, Maughan WL. Diastolic compliance of hypertrophied ventricle is not acutely altered by pharmacologic agents influencing active processes. Ann Intern Med. 1993; 119: 466–473.
120. Senzaki H, Isoda T, Paolocci N, Ekelund U, Hare JM, Kass DA. Improved mechanoenergetics and cardiac rest and reserve function of in vivo failing heart by calcium sensitizer EMD-57033. Circulation. 2000; 101: 1040–1048.
121. Feldman MD, Pak PH, Wu CC, Haber HL, Heesch CM, Bergin JD, Powers ER, Cowart TD, Johnson W, Feldman AM, Kass DA. Acute cardiovascular effects of OPC-18790 in patients with congestive heart failure. Time- and dose-dependence analysis based on pressure-volume relations. Circulation. 1996; 93: 474–483.
122. Kass DA, Midei M, Brinker J, Maughan WL. Influence of coronary occlusion during PTCA on end-systolic and end-diastolic pressure-volume relations in humans. Circulation. 1990; 81: 447–460.
123. Kass DA. Assessment of diastolic dysfunction. Invasive modalities. Cardiol Clin. 2000; 18: 571–586.[CrossRef][Medline] [Order article via Infotrieve]
124. Paulus WJ, Lorell BH, Craig WE, Wynne J, Murgo JP, Grossman W. Comparison of the effects of nitroprusside and nifedipine on diastolic properties in patients with hypertrophic cardiomyopathy: altered left ventricular loading or improved muscle inactivation? J Am Coll Cardiol. 1983; 2: 879–886.[Abstract]
125. Tyberg JV, Taichman GC, Smith ER, Douglas NWS, Smiseth O, Keon WJ. The relation between pericardial pressure and right atrial pressure: an intraoperative study. Circulation. 1986; 73: 428–432.
126. Serizawa T, Carabello BA, Grossman W. Effect of pacing-induced ischemia on left ventricular diastolic pressure-volume relations in dogs with coronary stenoses. Circ Res. 1980; 46: 430–439.
127. Paulus WJ, Serizawa T, Grossman W. Altered left ventricular diastolic properties during pacing-induced ischemia in dogs with coronary stenoses. Potentiation by caffeine. Circ Res. 1982; 50: 218–227.
128. Dauterman K, Pak PH, Nussbacher A, Arie S, Liu CP, Kass DA. Contribution of external forces to left ventricle diastolic pressure. Implications for the clinical use of the Frank-Starling law. Ann Intern Med. 1995; 122: 737–742.
129. Bronzwaer JG, De Bruyne B, Ascoop CA, Paulus WJ. Comparative effects of pacing-induced and balloon coronary occlusion ischemia on left ventricular diastolic function in man. Circulation. 1991; 84: 211–222.
130. Wittstein IS, Kass DA, Pak PH, Maughan WL, Fetics B, Hare JM. Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2001; 38: 429–435.
131. Friedrich SP, Lorell BH, Rousseau MF, Hayashida W, Hess OM, Douglas PS, Gordon S, Keighley CS, Benedict C, Krayenbuehl HP. Intracardiac angiotensin-converting enzyme inhibition improves diastolic function in patients with left ventricular hypertrophy due to aortic stenosis. Circulation. 1994; 90: 2761–2771.
132. Pak PH, Maughan WL, Baughman KL, Kass DA. Marked discordance between dynamic and passive diastolic pressure-volume relations in idiopathic hypertrophic cardiomyopathy. Circulation. 1996; 94: 52–60.
133. Cleland JG, Swedberg K, Follath F, Komajda M, Cohen-Solal A, Aguilar JC, Dietz R, Gavazzi A, Hobbs R, Korewicki J, Madeira HC, Moiseyev VS, Preda I, van Gilst WH, Widimsky J, Freemantle N, Eastaugh J, Mason J. The euroheart failure survey programme—a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J. 2003; 24: 442–463.
134. Hart CY, Redfield MM. Diastolic heart failure in the community. Curr Cardiol Rep. 2000; 2: 461–469.[Medline] [Order article via Infotrieve]
135. Masoudi FA, Havranek EP, Smith G, Fish RH, Steiner JF, Ordin DL, Krumholz HM. Gender, age, and heart failure with preserved left ventricular systolic function. J Am Coll Cardiol. 2003; 41: 217–223.
136. Zile MR. Heart failure with preserved ejection fraction: is this diastolic heart failure? J Am Coll Cardiol. 2003; 41: 1519–1522.
137. Burkhoff D, Maurer MS, Packer M. Heart failure with a normal ejection fraction: is it really a disorder of diastolic function? Circulation. 2003; 107: 656–658.
138. Zile MR, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP, Schaer GL, Ghali JK, Liebson PR. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation. 2001; 104: 779–782.
139. Kitzman DW. Diastolic dysfunction in the elderly. Genesis and diagnostic and therapeutic implications. Cardiol Clin. 2000; 18: 597–617.[CrossRef][Medline] [Order article via Infotrieve]
140. Gandhi SK, Powers JC, Nomeir AM, Fowle K, Kitzman DW, Rankin KM, Little WC. The pathogenesis of acute pulmonary edema associated with hypertension. N Engl J Med. 2001; 344: 17–22.
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 P. Knaapen, M. J. W. Gotte, W. J. Paulus, J. J. M. Zwanenburg, P. A. Dijkmans, R. Boellaard, J. T. Marcus, J. W. R. Twisk, C. A. Visser, A. C. van Rossum, et al. Does Myocardial Fibrosis Hinder Contractile Function and Perfusion in Idiopathic Dilated Cardiomyopathy? PET and MR Imaging Study. Radiology, August 1, 2006; 240(2): 380 - 388. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
A. F Leite-Moreira Current perspectives in diastolic dysfunction and diastolic heart failure. Heart, May 1, 2006; 92(5): 712 - 718. [Full Text] [PDF]
|
|
|
|
 |
|
 N. Paolocci, B. Tavazzi, R. Biondi, Y. A. Gluzband, A. M. Amorini, C. G. Tocchetti, M. Hejazi, P. M. Caturegli, J. Kajstura, G. Lazzarino, et al. Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 506 - 513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
C. S. Chung, D. M. Ajo, and S. J. Kovacs Isovolumic pressure-to-early rapid filling decay rate relation: model-based derivation and validation via simultaneous catheterization echocardiography J Appl Physiol, February 1, 2006; 100(2): 528 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O.-J. How, E. Aasum, D. L. Severson, W.Y. A. Chan, M. F. Essop, and T. S. Larsen Increased Myocardial Oxygen Consumption Reduces Cardiac Efficiency in Diabetic Mice Diabetes, February 1, 2006; 55(2): 466 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 M. W. Merx, C. Schafer, R. Westenfeld, V. Brandenburg, S. Hidajat, C. Weber, M. Ketteler, and W. Jahnen-Dechent Myocardial Stiffness, Cardiac Remodeling, and Diastolic Dysfunction in Calcification-Prone Fetuin-A-Deficient Mice J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3357 - 3364. [Abstract] [Full Text] [PDF]
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|
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|
|
|
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|
|
|
|
|
|
H. Fukuta, D. C. Sane, S. Brucks, and W. C. Little Statin Therapy May Be Associated With Lower Mortality in Patients With Diastolic Heart Failure: A Preliminary Report Circulation, July 19, 2005; 112(3): 357 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Ashikaga, J. W. Covell, and J. H. Omens Diastolic dysfunction in volume-overload hypertrophy is associated with abnormal shearing of myolaminar sheets Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2603 - H2610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Baicu, M. R. Zile, G. P. Aurigemma, and W. H. Gaasch Left Ventricular Systolic Performance, Function, and Contractility in Patients With Diastolic Heart Failure Circulation, May 10, 2005; 111(18): 2306 - 2312. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rysa, H. Leskinen, M. Ilves, and H. Ruskoaho Distinct Upregulation of Extracellular Matrix Genes in Transition From Hypertrophy to Hypertensive Heart Failure Hypertension, May 1, 2005; 45(5): 927 - 933. [Abstract] [Full Text] [PDF]
|
|
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|
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M Kruger, S Zittrich, C Redwood, N Blaudeck, J James, J Robbins, G Pfitzer, and R Stehle Effects of the mutation R145G in human cardiac troponin I on the kinetics of the contraction-relaxation cycle in isolated cardiac myofibrils J. Physiol., April 15, 2005; 564(2): 347 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Klein, A. Schaefer, D. Hilfiker-Kleiner, D. Oppermann, P. Shukla, A. Quint, E. Podewski, A. Hilfiker, F. Schroder, M. Leitges, et al. Increased Collagen Deposition and Diastolic Dysfunction but Preserved Myocardial Hypertrophy After Pressure Overload in Mice Lacking PKC{epsilon} Circ. Res., April 15, 2005; 96(7): 748 - 755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
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A. Borbely, J. van der Velden, Z. Papp, J. G.F. Bronzwaer, I. Edes, G. J.M. Stienen, and W. J. Paulus Cardiomyocyte Stiffness in Diastolic Heart Failure Circulation, February 15, 2005; 111(6): 774 - 781. [Abstract] [Full Text] [PDF]
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T. C. Gillebert, N. V. de Veire, M. L. De Buyzere, and J. D. Sutter Time intervals and global cardiac function. Use and limitations Eur. Heart J., December 2, 2004; 25(24): 2185 - 2186. [Full Text] [PDF]
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J. S. Ingwall and R. G. Weiss Is the Failing Heart Energy Starved?: On Using Chemical Energy to Support Cardiac Function Circ. Res., July 23, 2004; 95(2): 135 - 145. [Abstract] [Full Text] [PDF]
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