Clinical Cardiology: New Frontiers
`
`New Concepts in Diastolic Dysfunction and Diastolic
`Heart Failure: Part II
`Causal Mechanisms and Treatment
`
`Michael R. Zile, MD; Dirk L. Brutsaert, MD
`
`As described in Part I of this 2-part article,1 diastolic heart
`
`failure is common and causes significant alterations in
`prognosis. In Part II, experimental studies that have provided
`insight into the mechanisms that cause diastolic heart failure
`will be described.2–19 In addition, current treatment strategies
`and the design of future clinical trials of diastolic heart failure
`will be discussed. The development of truly effective therapy
`for diastolic heart failure depends on gaining a clear under-
`standing of the basic mechanisms that alter diastolic function
`and the ability to efficiently target
`these mechanisms to
`correct these abnormalities in diastolic function.
`
`Mechanisms That Cause Diastolic Dysfunction
`Conceptually, the mechanisms that cause abnormalities in
`diastolic function that lead to the development of diastolic
`heart failure can be divided into factors intrinsic to the
`myocardium itself (myocardial) and factors that are extrinsic
`to the myocardium (extramyocardial; Table 1). Myocardial
`factors can be divided into structures and processes within the
`cardiac muscle cell (cardiomyocyte), within the extracellular
`matrix (ECM) that surrounds the cardiac muscle cell, and that
`activate the autocrine or paracrine production of neurohor-
`mones. Each of these mechanisms are active in the major
`pathological processes that result in diastolic dysfunction and
`heart failure. Myocardial and extramyocardial mechanisms,
`cellular and extracellular mechanisms, and neurohumoral
`activation each play a role in the development of diastolic
`heart failure caused by ischemia, pressure-overload hypertro-
`phy, and restrictive and hypertrophic cardiomyopathy.
`
`Cardiomyocyte
`Diastolic dysfunction can be caused by mechanisms that are
`intrinsic to the cardiac muscle cells themselves. These include
`changes in calcium homeostasis caused by (1) abnormalities
`in the sarcolemmal channels responsible for short- and
`long-term extrusion of calcium from the cytosol, such as the
`sodium calcium exchanger and the calcium pump; (2) abnor-
`mal sarcoplasmic reticulum calcium (SR Ca2⫹) reuptake
`caused by a decrease in SR Ca2⫹ ATPase; and (3) changes in
`
`the phosphorylation state of the proteins that modify SR Ca2⫹
`ATPase function, such as phospholamban, calmodulin, and
`calsequestrin. Changes in any of these processes can result in
`increased cytosolic diastolic calcium concentration, prolon-
`gation in the calcium transient, and delayed and slowed
`diastolic decline in cytosolic calcium concentration. These
`changes have been shown to occur in cardiac disease and
`cause abnormalities in both active relaxation and passive
`stiffness.2
`The myofilament contractile proteins consist of thick-
`filament myosin and thin-filament actin proteins. Bound to
`actin are a complex of regulatory proteins that
`include
`tropomyosin and troponin (Tn) T, C, and I. During relaxation,
`ATP hydrolysis is required for myosin detachment from
`actin, calcium dissociation from Tn-C, and active sequestra-
`tion of calcium by the SR. Modification of any of these steps,
`the myofilament proteins involved in these steps, or the
`ATPase that catalyzes them can alter diastolic function.2– 6
`Thus, relaxation is an energy-consuming process. Energetic
`factors necessary to maintain normal diastolic function in-
`clude the requirement that the concentration of the products
`of ATP hydrolysis (ADP and inorganic phosphate [Pi]) must
`remain low and produce the appropriate relative ADP/ATP
`ratio.3– 6 Diastolic dysfunction will occur if the absolute
`concentration of ADP or Pi increases or if the relative ratio of
`ADP/ATP rises. Abnormalities in these energetics factors
`may be caused by a limited ability to recycle ADP to ATP
`because of a decrease in phosphocreatine.
`The cardiomyocyte cytoskeleton is composed of microtu-
`bules, intermediate filaments (desmin), microfilaments (ac-
`tin), and endosarcomeric proteins (titin, nebulin, ␣-actinin,
`myomesin, and M-protein).8 Changes in some of these
`cytoskeletal proteins have been shown to alter diastolic
`function.7,8,20 –25 Changes in titin isotypes have been shown to
`alter relaxation and viscoelastic stiffness. During contraction,
`potential energy is gained when titin is compressed, and
`during diastole, titin acts like viscoelastic springs, expends
`this stored potential energy, and provides a recoiling force to
`restore the myocardium to its resting length.20,21 In addition,
`
`From the Division of Cardiology (M.R.Z.), Department of Medicine, Medical University of South Carolina, The Gazes Cardiac Research Institute and
`the Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC; and the Departments of Physiology and Medicine (D.L.B.),
`University of Antwerp, Antwerp, Belgium.
`This is Part II of a 2-part article. Part I was published in the March 19, 2002, issue of Circulation (Circulation. 2002;105:1387–1393).
`Reprint requests to Michael R. Zile, MD, Cardiology Division, Medical University of South Carolina, 96 Jonathan Lucas St, Suite 816, Charleston,
`SC 29425. E-mail zilem@musc.edu
`(Circulation. 2002;105:1503-1508.)
`© 2002 American Heart Association, Inc.
`Circulation is available at http://www.circulationaha.org
`
`DOI: 10.1161/hc1202.105290
`
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`TABLE 1. Diastolic Heart Failure: Mechanisms
`
`Extramyocardial
`Hemodynamic load: early diastolic load, afterload
`Heterogeneity
`Pericardium
`Myocardial
`Cardiomyocyte
`Calcium homeostasis
`Calcium concentration
`Sarcolemmal and SR calcium transport function
`Modifying proteins (phospholamban, calmodulin, calsequestran)
`Myofilaments
`Tn-C calcium binding
`Tn-I phosphorylation
`Myofilament calcium sensitivity
`␣/␤-myosin heavy chain ATPase ratio
`Energetics
`ADP/ATP ratio
`ADP and Pi concentration
`Cytoskeleton
`Microtubules
`Intermediate filaments (desmin)
`Microfilaments (actin)
`Endosarcomeric skeleton (titin, nebulin)
`Extracellular matrix
`Fibrillar collagen
`Basement membrane proteins
`Proteoglycans
`MMP/TIMP
`Neurohormonal activation
`Renin-angiotensin-aldosterone
`Sympathetic nervous system
`Endothelin
`Nitric oxide
`Naturetic peptides
`
`MMP indicates matrix metalloproteinase; TIMP, tissue inhibitor of matrix
`metalloproteinase.
`
`titin extension during diastole is limited and protects the
`myocardium from being stretched too far beyond resting
`length. In experimental end-stage dilated cardiomyopathy,
`titin isoforms and distribution have been shown to change in
`a manner that confers an increase in stiffness.21 Likewise, an
`increase in microtubule density and distribution has been
`shown in some forms of pressure overload to act as a viscous
`load and increase myocardial and cardiomyocyte viscoelastic
`stiffness.7,22–25 This change in diastolic function is reversible
`when microtubules are acutely depolymerized by chemical or
`physical agents.7,22–25
`
`Extracellular Matrix
`Changes in the structures within the ECM can also affect
`diastolic function. The myocardial ECM is composed of 3
`important constituents: (1) fibrillar protein, such as collagen
`
`type I, collagen type III, and elastin; (2) proteoglycans; and
`(3) basement membrane proteins, such as collagen type IV,
`laminin, and fibronectin. It has been hypothesized that the
`most important component within the ECM that contributes
`to the development of diastolic heart failure is fibrillar
`collagen.11–15 The evidence that suggests that changes in
`ECM fibrillar collagen play an important role in the devel-
`opment of diastolic dysfunction and diastolic heart failure
`follows 3 lines. First, disease processes that alter diastolic
`function also alter ECM fibrillar collagen, particularly in
`terms of its amount, geometry, distribution, degree of cross-
`linking, and ratio of collagen type I versus collagen type III.
`Second, treatment of these disease processes, which is suc-
`cessful in correcting diastolic function, is associated with
`normalization of fibrillar collagen. Third, experiments in
`which a chronic alteration in collagen metabolism is accom-
`plished result in an alteration of diastolic function.26 –31 The
`role played by other fibrillar proteins, the basement mem-
`brane proteins, and the proteoglycans remains largely
`unexplored.
`The regulatory control of collagen biosynthesis and degra-
`dation has at
`least 3 major determinants:
`transcriptional
`regulation by physical, neurohumoral, and growth factors;
`posttranslational regulation, including collagen cross-linking;
`and enzymatic degradation.17–19 Collagen synthesis is altered
`by load, including preload and afterload; neurohumoral acti-
`vation, including the renin-angiotensin-aldosterone system
`(RAAS) and sympathetic nervous system; and growth factors.
`Collagen degradation is under the control of proteolytic
`enzymes, which includes a family of zinc-dependent en-
`zymes, the matrix metalloproteinases (MMPs).17–19 The bal-
`ance between synthesis and degradation results in the total
`collagen present in a given pathological state at a specific
`time. Changes in either synthesis or degradation and their
`regulatory processes have been shown to alter diastolic
`function and lead to the development of diastolic heart
`failure.
`
`Neurohumoral and Cardiac
`Endothelial Activation
`Both acutely and chronically, neurohumoral and cardiac
`endothelial activation and/or inhibition have been shown to
`alter diastolic function. Chronic activation of the RAAS has
`been shown to increase ECM fibrillar collagen and to be
`associated with increased stiffness. Inhibition of RAAS
`prevents or reverses this increase in fibrillar collagen and
`generally but not consistently reduces myocardial stiffness. In
`addition, acute activation or inhibition of neurohumoral and
`cardiac endothelial systems has been shown to alter relax-
`ation and stiffness.32 These acute pharmacological interven-
`tions act in a time frame too short to alter the ECM; therefore,
`their effect on diastolic function must be caused by direct
`action on the cardiomyocyte to alter 1 or more cellular
`determinants of diastolic function. For example, acute treat-
`ment of patients with pressure overload with an ACE inhib-
`itor, a direct NO donor, or an indirect endothelin-dependent
`NO donor caused left ventricular (LV) pressure decline and
`LV filling to be more rapid and complete and caused the LV
`pressure-versus-volume relationship to shift
`to the right,
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`
`TABLE 2. Diastolic Heart Failure: Treatment
`
`Symptom-targeted treatment
`Decrease pulmonary venous pressure
`Reduce LV volume
`Maintain atrial contraction
`Prevent tachycardia
`Improve exercise tolerance
`Use positive inotropic agents with caution
`Nonpharmacological treatment
`Restrict sodium to prevent volume overload
`Restrict fluid to prevent volume overload
`Perform moderate aerobic exercise to improve cardiovascular
`conditioning, decrease heart rate, and maintain skeletal muscle
`function
`Pharmacological treatment
`Diuretics, including loop diuretics, thiazides, spironolactone
`Long-acting nitrates
`␤-Adrenergic blockers
`Calcium channel blockers
`Renin-angiotensin-aldosterone antagonists, including ACE inhibitors,
`angiotensin II receptor blockers, and aldosterone antagonists
`Disease-targeted treatment
`Prevent/treat myocardial ischemia
`Prevent/regress ventricular hypertrophy
`Mechanism-targeted treatment
`Modify myocardial and extramyocardial mechanisms
`Modify intracellular and extracellular mechanisms
`
`decreasing stiffness.10 In addition, there is a cyclical release
`of NO in the heart that is most marked subendocardially and
`that peaks at the time of relaxation and filling. These brief
`bursts of NO release provide a beat-to-beat modulation of
`relaxation and stiffness.9
`
`Treatment
`
`General Approach
`Unfortunately, there have been no randomized, double-blind,
`placebo-controlled, multicenter trials performed in patients
`with diastolic heart failure. Consequently, the guidelines for
`the management of diastolic heart failure are based on clinical
`investigations in relatively small groups of patients, clinical
`experience, and concepts based on pathophysiological mech-
`anisms.33–36 The treatment regimen outlined below and in
`Table 2 applies to those patients with symptomatic diastolic
`heart failure. Whether treatment of asymptomatic diastolic
`dysfunction confers any benefit has not been examined.
`Treatment of diastolic heart failure can be framed in 3
`steps. First,
`treatment should target symptom reduction,
`principally by decreasing pulmonary venous pressure at rest
`and during exertion. Both nonpharmacological and pharma-
`cological approaches proposed but not proven to be effective
`in targeting symptoms are listed in Table 2. Second, treatment
`should target the pathological disease that caused the diastolic
`heart failure. For example, coronary artery disease, hyperten-
`sive heart disease, and aortic stenosis provide relatively
`
`Zile and Brutsaert
`
`Diastolic Heart Failure
`
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`
`specific therapeutic targets, such as lowering of blood pres-
`sure, induction of hypertrophy regression, performance of
`aortic valve replacement, and treatment of ischemia by
`increasing myocardial blood flow and reducing myocardial
`oxygen demand. Third, treatment should target the underly-
`ing mechanisms that are altered by the disease processes.
`
`Symptom-Targeted Treatment
`
`Decrease Diastolic Pressure
`The initial step in treating patients presenting with diastolic
`heart failure is to reduce pulmonary congestion by decreasing
`LV volume, maintaining synchronous atrial contraction, and
`increasing the duration of diastole by reducing heart rate. By
`decreasing LV diastolic volumes, LV pressures “slide” down
`the curvilinear diastolic pressure-volume relationship toward
`a lower,
`less steep portion of this curve. LV diastolic
`pressures can be decreased by reducing total blood volume
`(eg, through fluid and sodium restriction or use of diuretics),
`decreasing central blood volume (nitrates), and blunting
`neurohumoral activation. Treatment with diuretics and ni-
`trates should be initiated at low doses to avoid hypotension
`and fatigue. Hypotension can be a significant problem,
`because these patients have a very steep diastolic pressure-
`volume curve such that a small change in diastolic volume
`causes a large change in pressure and cardiac output.
`Both basic and clinical studies suggest that hypertrophy is
`associated with activation of neurohumoral systems such as
`the RAAS.11,12 One mechanism that causes fluid retention
`and an increase in central and systemic volume is activation
`of these neurohumoral systems. Therefore,
`treatment for
`diastolic heart failure might include agents such as ACE
`inhibitors, AT1 receptor antagonists, and aldosterone antago-
`nists. In addition to promoting fluid retention, neurohumoral
`activation can have direct effects on cellular and extracellular
`mechanisms that contribute to the development of diastolic
`heart failure. Modulation of neurohumoral activation may
`also affect fibroblast activity, interstitial fibrosis, intracellular
`calcium handling, and myocardial stiffness.
`Tachycardia is poorly tolerated in patients with diastolic
`heart failure for several reasons. First, rapid heart rates cause
`an increase in myocardial oxygen demand and a decrease in
`coronary perfusion time, which can promote ischemic dia-
`stolic dysfunction even in the absence of epicardial coronary
`disease, especially in patients with LV hypertrophy. Second,
`a shortened diastole may cause incomplete relaxation be-
`tween beats, resulting in an increase in diastolic pressure
`relative to volume. Third, hearts with diastolic dysfunction
`exhibit a flat or even negative relaxation velocity–versus–
`heart rate relationship, so that as heart rate increases, relax-
`ation rate does not increase or may even decrease, which can
`then cause diastolic pressures to increase.37–39 ␤-Blockers and
`some calcium channel blockers can thus be used to prevent
`excessive tachycardia and produce a relative bradycardia.
`Although the optimal heart rate must be individualized, an
`initial goal might be a resting heart rate of ⬇60 to 70 bpm
`with a blunted exercise-induced increase in heart rate.40
`
`Improve Exercise Tolerance
`Patients with diastolic heart failure have a marked limitation
`in exercise tolerance. There are a number of mechanisms
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`TABLE 3. Randomized Clinical Trials for Diastolic Heart Failure
`
`Trial
`
`CHARM
`
`Wake Forest
`
`MCC-135
`
`Inclusion
`CHF; EF⬎40%
`
`Mortality;
`hospitalization
`Hypertension; EF⬎50% Exercise tolerance;
`VO2 max
`Exercise tolerance;
`remodeling
`
`CHF; EF⬎40%
`
`End Points
`
`Duration
`
`Drug
`
`Sponsor
`
`3 y
`
`Candesartan; placebo
`
`AstraZeneca LP
`
`6 mo
`
`6 mo
`
`Losartan;
`hydrochlorothiazide
`MCC-135; placebo
`
`Merck
`
`Mitsubishi-Tokyo
`
`CHARM indicates Candesartan Cilexetil in Heart Failure Assessment of Reduction in Mortality and Morbidity; CHF,
`congestive heart failure; EF, ejection fraction; Wake Forest, the effect of losartan versus hydrochlorothiazide on
`exercise tolerance in patients with exercise-induced hypertension and asymptomatic diastolic dysfunction; VO2max,
`maximum oxygen consumption; and MCC-135, a phase II, double-blind, randomized, placebo-controlled, dose-
`comparative study of the efficacy, tolerability, and safety of MCC-135 in subjects with chronic heart failure, New York
`Heart Association class II/III.
`
`responsible for this limitation. In patients with diastolic heart
`failure, the ability to use the Frank-Starling mechanism is
`limited despite the increased filling pressures because in-
`creased diastolic stiffness prevents the increase in LV end-
`diastolic volume that normally accompanies exercise.41– 44
`The abnormal relaxation velocity–versus–heart rate relationship
`that exists in patients with diastolic heart failure prevents
`augmentation of relaxation velocity as heart rate increases during
`exercise.37–39 As a result, during exercise, diastolic pressure
`increases, the stroke volume fails to rise, and patients experience
`dyspnea and fatigue. In patients with diastolic heart failure, there
`is frequently an exaggerated rise in blood pressure in response to
`exercise that increases LV load and in turn further impairs
`myocardial relaxation and filling.45
`␤-Blockers, calcium channel blockers, and AT1 antagonists
`may have a salutary effect on symptoms and exercise capac-
`ity in many patients with diastolic heart failure. However, the
`beneficial effect of these agents on exercise tolerance is not
`always paralleled by improved LV diastolic function or
`increased relaxation rate. Nonetheless, a number of small
`clinical trials have shown that the use of these agents results
`in improvement in exercise capacity in patients with diastolic
`heart failure.46 – 48
`
`Use Positive Inotropic Drugs With Caution
`Positive inotropic agents are generally not used in the
`treatment of patients with isolated diastolic heart failure
`because the ejection fraction is preserved, and there appears
`to be little potential benefit. Moreover, such drugs have the
`potential to worsen the pathophysiological processes that
`cause diastolic heart failure. In contrast to long-term use,
`positive inotropic drugs may be beneficial in the short-term
`treatment of pulmonary edema associated with diastolic heart
`failure because they enhance SR function, promote more
`rapid and complete relaxation,
`increase splanchnic blood
`flow, increase venous capacitance, and facilitate diuresis.49 –52
`However, even short-term treatment with these agents may
`adversely affect energetics, induce ischemia, raise heart rate,
`and induce arrhythmias. Therefore, these agents should be
`used with caution, if they are used at all.
`Results of the Digitalis Investigation Group trial53 sug-
`gested that patients with heart failure and a normal ejection
`fraction may have fewer symptoms and fewer hospitaliza-
`
`tions if they are treated with digitalis. However, a detailed
`analysis of these data in patients with a preserved ejection
`fraction has not been published, and a beneficial effect has
`not been proved. Digitalis may produce an increase in systolic
`energy demands while adding to a relative calcium overload
`in diastole. These effects may not be clinically apparent under
`many circumstances, but during hemodynamic stress or
`ischemia, digitalis may promote or contribute to diastolic
`dysfunction.53 Therefore, the utility of digitalis in the treat-
`ment of diastolic heart failure remains unclear.
`
`Differences Between Pharmacological Treatment
`of Systolic and Diastolic Heart Failure
`With a number of notable exceptions, many of the drugs used
`to treat diastolic heart failure are in fact the same as those
`used to treat systolic heart failure. However, the rationale for
`their use, the pathophysiological process that is being altered
`by the drug, and the dosing regimen may be entirely different
`depending on whether the patient has systolic or diastolic
`heart failure. For example, ␤-blockers are now recommended
`for the treatment of both systolic and diastolic heart failure. In
`diastolic heart failure, however, ␤-blockers are used to
`decrease heart rate, increase the duration of diastole, and
`modify the hemodynamic response to exercise. In systolic
`heart failure, ␤-blockers are used chronically to increase
`inotropic state and modify LV remodeling. In systolic heart
`failure, ␤-blockers must be titrated slowly and carefully over
`an extended time period. This is generally not necessary in
`diastolic heart failure. Diuretics are used in the treatment of
`both systolic and diastolic heart failure. However, the doses
`of diuretics used to treat diastolic heart failure are generally
`smaller than the doses used in systolic heart failure. Some
`drugs are used only to treat either systolic or diastolic heart
`failure but not both. For example, calcium channel blockers
`such as diltiazem, nifedipine, and verapamil have no place in
`the treatment of systolic heart failure. By contrast, each of
`these has been proposed as being useful in the treatment of
`diastolic heart failure.
`
`Mechanism-Targeted Treatment (Future Directions)
`Conceptually, an ideal therapeutic agent should target the
`underlying mechanisms that cause diastolic heart failure.
`Therefore, a therapeutic agent might improve calcium ho-
`
`Ex. 2030-0004
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`

`
`meostasis and energetics, blunt neurohumoral activation, or
`prevent and regress fibrosis. Fortunately, some pharmaceuti-
`cal agents that fit these design characteristics are already in
`existence, and many more are under development. Unfortu-
`nately, randomized, double-blind, placebo-controlled, multi-
`center trials that examine the efficacy of these agents used
`either singly or in combination have been slow to develop.
`Difficulties that have prevented these kinds of studies have
`included a lack of recognition of the importance of diastolic
`heart failure, an inability to define a homogeneous study
`population, a lack of agreement on the definition and diag-
`nostic criteria for diastolic heart failure, and a perception that
`there would be a marginal return on investment for funding
`these kinds of studies. There is now, however, reason for a
`great deal of optimism. Diastolic heart failure is now recog-
`nized as an important problem, guidelines for diagnosis have
`been developed, and the pharmaceutical industry has sup-
`ported (and it is hoped that in the near future, government
`agencies will support) randomized, double-blind, placebo-
`controlled, multicenter trials. Three such trials are now under
`way (Table 3). Two of these trials target neurohumoral
`activation in the RAAS by inhibiting the angiotensin II
`receptor (Candesartan cilexetil in Heart failure Assessment of
`Reduction in Mortality and morbidity [CHARM] and Wake
`Forest). The third study targets intracellular calcium ho-
`meostasis using an agent that is proposed to improve SR
`calcium reuptake (MCC-135). With these 3 studies, and
`others that are currently under development, an effective
`treatment for diastolic heart failure will be more completely
`defined.
`
`Acknowledgments
`The authors thank Bev Ksenzak for her help in the preparation of this
`manuscript. In addition, the authors thank William H. Gaasch, MD,
`for his critique of this review. Many of the concepts discussed in this
`review were originally formulated and later validated by Dr Gaasch,
`his collaborators, and his students. The authors are grateful for his
`unique insights and his ability to explain complex ideas in easily
`understood terms.
`
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