Clinical Cardiology: New Frontiers
`
`New Concepts in Diastolic Dysfunction and
`Diastolic Heart Failure: Part I
`Diagnosis, Prognosis, and Measurements of Diastolic Function
`
`Michael R. Zile, MD; Dirk L. Brutsaert, MD
`
`There is growing recognition that congestive heart failure
`
`(CHF) caused by a predominant abnormality in diastolic
`function (ie, diastolic heart failure) is both common and
`causes significant morbidity and mortality. However, there is
`continued controversy surrounding the definition of diastolic
`dysfunction and the diagnostic criteria for diastolic heart
`failure. As a result, clinical therapeutic trials have been slow
`to develop and difficult to design. Fortunately, these contro-
`versies are yielding to an emerging consensus. Recent clinical
`studies have provided sufficient data to develop standardized
`diagnostic criteria to define diastolic heart failure.1– 4 Exper-
`imental studies have provided increased insight
`into the
`mechanisms that cause diastolic heart failure.5–22 Together,
`these clinical and experimental studies are being used to
`design targeted clinical trials to test effective treatments for
`diastolic heart failure. The purpose of this 2-part article is to
`provide a perspective on these issues, highlight new research,
`and introduce emerging ideas. Part 1 will focus on the criteria
`used to diagnose diastolic heart failure, the effects of diastolic
`heart failure on prognosis, and measurements used to assess
`diastolic function. Part 2 will describe the mechanisms that
`cause diastolic heart failure and discuss approaches to
`treatment.
`
`Definitions
`Differentiating Diastolic Dysfunction From
`Diastolic Heart Failure
`Heart failure is a clinical syndrome characterized by symp-
`toms and signs of increased tissue/organ water and decreased
`tissue/organ perfusion. Standardized criteria to diagnose heart
`failure have been developed, perhaps the best validated of
`which come from the Framingham Study.23 Definition of the
`mechanisms that cause this clinical syndrome requires mea-
`surement of both systolic and diastolic function. When heart
`failure is accompanied by a predominant or isolated abnor-
`mality in diastolic function, this clinical syndrome is called
`diastolic heart failure.
`
`Diastolic dysfunction refers to a condition in which abnor-
`malities in mechanical function are present during diastole.
`Abnormalities in diastolic function can occur in the presence
`or absence of a clinical syndrome of heart failure and with
`normal or abnormal systolic function. Therefore, whereas
`diastolic dysfunction describes an abnormal mechanical prop-
`erty, diastolic heart failure describes a clinical syndrome.
`
`Definition of Diastolic Heart Failure
`Diastolic heart failure is a clinical syndrome characterized by
`the symptoms and signs of heart failure, a preserved ejection
`fraction (EF), and abnormal diastolic function. From a con-
`ceptual perspective, diastolic heart failure occurs when the
`ventricular chamber is unable to accept an adequate volume
`of blood during diastole, at normal diastolic pressures and at
`volumes sufficient to maintain an appropriate stroke volume.
`These abnormalities are caused by a decrease in ventricular
`relaxation and/or an increase in ventricular stiffness. Diastolic
`heart failure can produce symptoms that occur at rest (New
`York Heart Association [NYHA] class IV), symptoms that
`occur with less than ordinary physical activity (NYHA class
`III), or symptoms that occur with ordinary physical activity
`(NYHA class II).
`
`Definition of Diastolic Dysfunction
`Conceptually, diastole encompasses the time period during which
`the myocardium loses its ability to generate force and shorten and
`returns to an unstressed length and force. By extension, diastolic
`dysfunction occurs when these processes are prolonged, slowed, or
`incomplete. Whether this time period is defined by the classic
`concepts of Wiggers or the constructs of Brutsaert,24 the measure-
`ments that reflect changes in this normal function generally depend
`on the onset, rate, and extent of ventricular pressure decline and
`filling and the relationship between pressure and volume or stress
`and strain during diastole. Moreover, if diastolic function is truly
`normal, these measurements must remain normal both at rest and
`during the stress of a variable heart rate, stroke volume, end-dia-
`stolic volume, and blood pressure.
`
`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 I of a 2-part article. Part II will be published in the March 26, 2002, issue of Circulation.
`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;105:1387–1393.)
`© 2002 American Heart Association, Inc.
`Circulation is available at http://www.circulationaha.org
`
`DOI: 10.1161/hc1102.105289
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`Figure 1. Pressure-volume loops contrasting iso-
`lated diastolic heart failure (A) with systolic heart
`failure (B) and combined systolic and diastolic
`heart failure (C). A normal patient (solid line) is
`compared with a patient with heart failure before
`(dashed line) and after (dotted line) treatment. HF
`indicates heart failure.
`
`Definition of Combined Systolic and Diastolic
`Heart Failure
`Diastolic heart failure can occur alone (Figure 1A) or in
`combination with systolic heart failure (Figure 1, B and C). In
`patients with isolated diastolic heart failure (Figure 1A), the
`only abnormality in the pressure-volume relationship occurs
`during diastole, when there are increased diastolic pressures
`with normal diastolic volumes. When diastolic pressure is
`markedly elevated, patients are symptomatic at rest or with
`minimal exertion (NYHA class III to IV). With treatment,
`diastolic volume and pressure can be reduced, and the patient
`becomes less symptomatic (NYHA class II), but the diastolic
`pressure-volume relationship remains abnormal.
`In patients with systolic heart failure (Figure 1B), there are
`abnormalities in the pressure-volume relationship during
`systole that include decreased EF, stroke volume, and stroke
`work. In addition, there are changes in the diastolic portion of
`the pressure-volume relationship. These changes result in
`
`increased diastolic pressures in symptomatic patients, which
`indicate the presence of combined systolic and diastolic heart
`failure. Whereas the diastolic pressure-volume relationship
`may reflect a more compliant chamber, increased diastolic
`pressure and abnormal relaxation reflect
`the presence of
`abnormal diastolic function. Thus, all patients with systolic
`heart failure and elevated diastolic pressures in fact have
`combined systolic and diastolic heart failure.
`Another form of combined systolic and diastolic heart
`failure is also possible (Figure 1C). Patients may have only a
`modest decrease in EF and a modest increase in end-diastolic
`volume but a marked increase in end-diastolic pressure and a
`diastolic pressure-volume relationship that reflects decreased
`chamber compliance. Therefore, virtually all patients with
`symptomatic heart failure have abnormalities in diastolic
`function, those with a normal EF have isolated diastolic heart
`failure, and those with a decreased EF have combined systolic
`and diastolic heart failure.
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`TABLE 1. Prevalence of Specific Symptoms and Signs in
`Systolic vs Diastolic Heart Failure
`
`Diastolic
`Heart Failure
`(EF⬎50%)
`
`Systolic
`Heart Failure
`(EF⬍50%)
`
`Symptoms
`Dyspnea on exertion
`Paroxysmal nocturnal dyspnea
`Orthopnea
`Physical examination
`Jugular venous distension
`Rales
`Displaced apical impulse
`S3
`S4
`Hepatomegaly
`Edema
`Chest radiograph
`Cardiomegaly
`Pulmonary venous hypertension
`
`85
`55
`60
`
`35
`72
`50
`45
`45
`15
`30
`
`90
`75
`
`96
`50
`73
`
`46
`70
`60
`65
`66
`16
`40
`
`96
`80
`
`Data are presented as percent of patients in each group with the listed
`symptom or sign of heart failure.25,26 There were no statistically significant
`differences between patients with an EF ⬎50% vs ⬍50%.
`
`Diagnosis
`The diagnosis of diastolic heart failure cannot be made “at the
`bedside.” Differentiation between systolic and diastolic heart
`failure cannot be made on the basis of history, physical
`examination, ECG, or chest radiograph alone, because mark-
`ers from these examinations occur with the same relative
`frequency in both systolic and diastolic heart failure (Table
`1).25,26 It is for this reason that diagnostic criteria based on
`measurements of systolic and diastolic function have been
`developed.
`The Working Group for the European Society of Cardiol-
`ogy proposed that “[a] diagnosis of primary diastolic heart
`failure requires three obligatory conditions to be simulta-
`neously satisfied: 1) presence of signs or symptoms of
`congestive heart failure (CHF); 2) presence of normal or only
`mildly abnormal left ventricular (LV) systolic function; 3)
`evidence of abnormal LV relaxation, filling, diastolic disten-
`sibility, or diastolic stiffness.”1 These diagnostic criteria have
`been criticized for 3 reasons. The first obligatory condition
`requires the presence of signs “or” symptoms of CHF;
`however, it is well recognized that the mere presence of
`breathlessness and fatigue is not specific for the presence of
`CHF. It would be more prudent to include the term signs
`“and” symptoms of CHF or to use specific diagnostic criteria
`such as the Framingham criteria. The second criticism re-
`volves around the term “systolic function.” The working
`group defined systolic function as being normal when LV EF
`is ⱖ45%. Because EF is not a measure of contractility or a
`load-independent measurement of systolic function, the sec-
`ond requirement would be more precise if stated simply as a
`normal EF. The third difficulty is the requirement that a
`measurable abnormality in diastolic function be present.
`Similar to measurements of systolic function, measurements
`
`Zile and Brutsaert
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`Diastolic Heart Failure
`
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`of ventricular relaxation, filling, and compliance are load
`dependent. Therefore, their poor specificity, sensitivity, and
`predictive accuracy, as well as the difficult practical aspects
`of making measurements of diastolic function,
`limit
`the
`application of this requirement in the clinical setting.
`Vasan and Levy2 proposed an expansion and refinement of
`these diagnostic criteria by suggesting that they be divided
`into definite, probable, and possible diastolic heart failure.
`Definite diastolic heart failure requires definitive evidence of
`CHF; objective evidence of normal systolic function, with an
`EF ⬎50% within 72 hours of the CHF event; and objective
`evidence of diastolic dysfunction on cardiac catheterization.
`If objective evidence of diastolic dysfunction is lacking but
`the first 2 criteria are present, this fulfills the criteria for
`probable diastolic heart failure. If the first criterion is present
`and EF is ⬎50% but not assessed within 72 hours of the CHF
`event, this fulfills the criteria for possible diastolic heart
`failure. Possible diastolic heart failure can be upgraded to
`probable diastolic heart failure if one of a number of
`additional criteria is present.
`The clinical application of these guidelines is limited both
`because they are complex and because they are empiric.
`However, subsequent studies suggested methods to simplify
`the diagnostic criteria and provided objective data to validate
`them.3,4 Studies by Gandi et al3 addressed the requirement for
`the presence of an EF ⱖ50% within 72 hours of the CHF
`event. This study demonstrated that in patients presenting to
`the emergency room with acute pulmonary edema and sys-
`tolic hypertension (systolic blood pressure ⬎160 mm Hg),
`there were no significant differences between EF measured
`echocardiographically at
`the time of presentation to the
`emergency room, when patients had active CHF, and 72
`hours after the event, at a time at which patients were
`clinically stable and no longer in symptomatic heart failure.
`Therefore, under most circumstances, EF does not need to be
`measured coincident with the heart failure event. Measure-
`ment of EF within 72 hours is sufficient to meet diagnostic
`criteria for diastolic heart failure. The one possible exception
`to the use of this approach may be the presence of acute
`ischemia. However, ⬎50% of the patients studied by Gandi et
`al3 had segmental wall-motion abnormalities on echocardio-
`gram consistent with ischemic heart disease. Two patients
`had transient segmental wall-motion abnormalities that nor-
`malized with resolution of the pulmonary edema. None of
`these patients had a significant change in EF after 72 hours.
`It is possible that patients with pulmonary edema caused by
`acute ischemia are unable to generate high systolic pressure
`and/or have resolution of the ischemia before echocardio-
`graphic study; however, although it is unknown how often
`this occurs, it is likely to be infrequent. Thus, based on this
`study,
`to meet
`the diagnostic criteria for diastolic heart
`failure, EF must be ⬎50% within 72 hours of the heart failure
`event. Whether this measurement can be delayed beyond 72
`hours remains to be determined.
`Zile et al4 examined the necessity of obtaining objective
`evidence of diastolic dysfunction. In this study, patients with
`a history of CHF who fulfilled the Framingham criteria and
`had an EF ⱖ50% underwent diagnostic left heart catheter-
`ization and simultaneous Doppler echocardiography. None of
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`TABLE 2. Diastolic Heart Failure: Effects of Age on Prevalence
`and Prognosis
`
`Prevalence
`Mortality
`Morbidity
`
`⬍50
`15
`15
`25
`
`Age, y
`
`50 –70
`
`33
`33
`50
`
`⬎70
`50
`50
`50
`
`All values are percentages.
`Prevalence indicates percentage of all heart failure patients presenting with
`diastolic heart failure; Mortality, 5-year mortality rate; and Morbidity, 1-year
`rate of hospital admission for heart failure. The percentage values given in this
`table are approximate and rounded figures based on multiple studies.24,27– 40
`
`these patients had evidence of coronary heart disease. Fewer
`than half of the patients had LV hypertrophy (defined as LV
`mass ⱖ125 g/m2). In this group of patients, 92% had at least
`1 pressure-derived abnormality in diastolic function (includ-
`ing an LV end-diastolic pressure ⬎16 mm Hg), 94% had at
`least 1 Doppler echocardiography– derived abnormality in
`diastolic function (including a deceleration time ⬎250 ms),
`and 100% had at least 1 pressure or Doppler abnormality in
`diastolic function. Therefore, objective measurements of LV
`diastolic function serve to confirm rather than establish the
`diagnosis of diastolic heart failure. These authors concluded
`that the diagnosis of diastolic heart failure can be made
`without measurement of diastolic function if 2 criteria are
`present: (1) symptoms and signs of heart failure (Framingham
`criteria) and (2) LV EF ⬎50%.
`
`Prognosis
`
`Prevalence
`The prevalence of diastolic dysfunction without diastolic
`heart failure and the prevalence of mild diastolic heart failure
`(NYHA class II) are not known. Early studies suggested that
`as many as one third of patients presenting with overt CHF
`have a normal EF and, therefore, isolated diastolic heart
`failure.27–29 However, more recent studies have made it clear
`that both the prevalence and prognosis (discussed below) of
`diastolic heart failure are dependent on age, sex, methods
`used to diagnose diastolic heart failure, study design, the
`value of EF that is used as a cutoff value, and the underlying
`clinical disease process that caused the diastolic heart fail-
`ure.30 –37 Whereas these determinants are largely interdepen-
`dent, the most important determinant is likely to be age
`(Table 2). Studies examining prevalence of diastolic heart
`failure in hospitalized patients or in patients undergoing
`outpatient diagnostic screening and prospective community-
`based studies have shown that in patients ⬎70 years old, the
`prevalence of diastolic heart failure approaches 50%.30 –37
`
`Mortality
`The prognosis of patients with diastolic heart failure, al-
`though less ominous than that for patients with systolic heart
`failure, does exceed that
`for age-matched control pa-
`tients.38 – 40 The annual mortality rate for patients with dia-
`stolic heart failure approximates 5% to 8%. In comparison,
`the annual mortality rate for patients with systolic heart
`failure approximates 10% to 15%, whereas that for age-
`
`matched controls approaches 1%. In patients with diastolic
`heart failure, the prognosis is also affected by the pathological
`origin of the disease. Thus, when patients with coronary
`artery disease are excluded, the annual mortality rate for
`isolated diastolic heart failure approximates 2% to 3%.39,40
`The other determinants of mortality include age, EF cutoff,
`and study design. Like prevalence, these are interactive, with
`the most important determinant being age (Table 2). In fact,
`an increasing amount of data suggests that in patients ⬎70
`years old, the mortality rates for systolic and diastolic heart
`failure are nearly equivalent.30 –37
`
`Morbidity
`Morbidity from diastolic heart failure is quite high, which
`necessitates frequent outpatient visits, hospital admissions,
`and the expenditure of significant healthcare resources. The
`1-year readmission rate approaches 50% in patients with
`diastolic heart failure. This morbidity rate is nearly identical
`to that for patients with systolic heart failure.30 –37
`
`Measurement of Diastolic Function
`Measurements of diastolic function can be divided into those
`that reflect the process of active relaxation and those that
`reflect passive stiffness. This division is in some ways
`arbitrary, because structures and processes that alter relax-
`ation can also result in measurable abnormalities in stiffness.
`However, this division is pragmatic and provides a necessary
`scaffold on which to develop methods of measurement.
`
`Relaxation
`Diastole encompasses the period during which the myo-
`cardium loses its ability to generate force and shorten and
`then returns to resting force and length. Relaxation occurs in
`a series of energy-consuming steps beginning with the release
`of calcium from troponin C, detachment of the actin-myosin
`cross-bridge, phosphorylation of phospholamban, sarcoplas-
`mic reticulum calcium ATPase–induced calcium sequestra-
`tion into the sarcoplasmic reticulum, sodium/calcium ex-
`changer–induced extrusion of calcium from the cytoplasm,
`slowing of cross-bridge cycling rate, and extension of the
`sarcomere to its rest length.5–9 Adequate energy supplies and
`the mechanisms to regenerate them must be present for this
`process to occur at a sufficient rate and extent.6,8,9 The rate of
`and extent to which these cellular processes occur determine
`the rate and extent of active ventricular relaxation. At the
`chamber level, this process results in LV pressure decline at
`constant volume (isovolumic relaxation), then LV chamber
`filling, which occurs with variable LV pressures (auxotonic
`relaxation). Measurements made during auxotonic relaxation
`are affected both by active relaxation and by passive stiffness.
`Isovolumic relaxation can be quantified by measurement of
`LV pressure with a high-fidelity micromanometer catheter
`and calculation of the peak instantaneous rate of LV pressure
`decline, peak (⫺) dP/dt, and the time constant of isovolumic
`LV pressure decline, ␶.41– 43 When the natural log of LV
`diastolic pressure is plotted versus time, ␶ equals the inverse
`slope of this linear relation. Stated in more conceptual terms,
`␶ is the time that
`it
`takes for LV pressure to fall by
`approximately two thirds of its initial value. When isovolu-
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`Figure 2. LV and left atrial (LA) pressures during diastole, transmitral Doppler LV inflow velocity, pulmonary vein Doppler velocity, and
`Doppler tissue velocity. IVRT indicates isovolumic relaxation time; Dec. Time, e-wave deceleration time; E, early LV filling velocity; A,
`velocity of LV filling contributed by atrial contraction; PVs, systolic pulmonary vein velocity; PVd, diastolic pulmonary vein velocity; PVa,
`pulmonary vein velocity resulting from atrial contraction; Sm, myocardial velocity during systole; Em, myocardial velocity during early fill-
`ing; and Am, myocardial velocity during filling produced by atrial contraction.
`
`mic pressure decline is slowed, ␶ is prolonged and the
`numerical value of ␶increases. Noninvasive estimates of total
`isovolumic relaxation time can be made by echocardiograph-
`ic techniques. No index of relaxation (isovolumic or auxo-
`tonic) can be considered an index of “intrinsic” relaxation
`rate unless loading conditions (and other modulators) are held
`constant or are at
`least specified. One practical way to
`overcome this limitation is to examine indices of relaxation
`over a range of loads. Afterload can be altered acutely by
`mechanical or pharmacological methods. Abnormal relax-
`ation is indicated by the shift in the position of the relaxation
`rate–versus-afterload relationship, where relaxation is slowed
`at any equivalent systolic stress.44
`Whereas active relaxation may be regarded in the strictest
`sense as an early diastolic event, the time of onset of this
`process depends, at least in part, on systolic events such as the
`duration of contraction.24 Conversely, the time of onset of
`relaxation can modify systolic events. Therefore, the rate and
`extent of relaxation,
`in addition to being dependent on
`ventricular load, are also dependent on the duration of
`systole, the time of onset of relaxation, and the time during
`systole in which load is altered.24,44,45 If the onset of relax-
`ation is delayed (for example, by an increase in load early in
`systole), this may prolong the duration of systole, increase
`cardiac work during systole, and prolong relaxation. Con-
`versely, if the onset of relaxation occurs earlier (for example,
`because of an increase in load late in systole), this may
`
`shorten the duration of systole and may abbreviate relaxation.
`Thus, a complex interaction between events traditionally
`considered to occur during systole can affect the measure-
`ment and interpretation of active relaxation.
`The auxotonic LV filling phases of diastole can be char-
`acterized by Doppler echocardiography or by radionuclide,
`conductance, or MRI techniques. Whereas each technique has
`advantages and disadvantages, all assess diastolic function by
`measuring indices of volume transients during ventricular
`filling. However, like all relaxation indices, auxotonic indices
`must be interpreted in light of simultaneous changes in load,
`both afterload and filling load (load present during fill-
`ing).24,44,46 For example, the precise pattern of early and late
`diastolic transmitral flow velocities will depend on factors
`that govern instantaneous atrial and LV pressures before and
`after mitral valve opening and the resultant atrial-ventricular
`pressure gradient (filling load). Thus, it is not surprising that
`interventions or pathological conditions that
`increase left
`atrial pressure increase early transmitral flow velocities,
`whereas interventions that reduce left atrial pressure reduce
`early filling velocities. To correctly interpret changes in
`transmitral flow velocities, concomitant changes in filling
`load must be considered. Additional indices that may be less
`sensitive to and may indicate changes in load are currently
`under investigation.47–52 These include pulmonary venous
`flow rates, transmitral propagation velocity, and tissue Dopp-
`ler velocity (Figure 2).
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`Stiffness
`In addition to active relaxation, passive viscoelastic
`properties contribute to the process that returns the myo-
`cardium to its resting force and length. These passive
`viscoelastic properties are dependent on both intracellular
`and extracellular structures (see “Mechanisms” in part 2 of
`this report53). Changes in the stiffness of the ventricular
`chamber can be assessed by examination of the pressure
`and volume relationship during diastole. Chamber stiffness
`is determined both by the stiffness of the constituent
`myocardium and by LV mass and the LV mass/volume
`ratio. Changes in myocardial stiffness can be assessed by
`examination of the myocardial stress, strain, and strain-rate
`relationships during diastole.
`Chamber stiffness can be quantified by examination of the
`relationship between diastolic pressure and volume. The
`operating stiffness at any point along a given pressure-
`volume curve is equal to the slope of a tangent drawn to the
`curve at
`that point (dP/dV). Operating stiffness changes
`throughout filling; stiffness is lower at smaller volumes and
`higher at larger volumes (volume-dependent change in dia-
`stolic pressure and stiffness). Because the diastolic pressure-
`volume relationship is curvilinear and generally exponential,
`the relationship between dP/dV and pressure is linear; the
`slope (Kc), is called the modulus of chamber stiffness (or
`chamber stiffness constant) and can be used as a single
`numerical value to quantify chamber stiffness. When overall
`chamber stiffness is increased, the pressure-volume curve
`shifts to the left, the slope of the dP/dV-versus-pressure
`relationship becomes steeper, and Kc is increased (volume-
`independent change in diastolic pressure and stiffness). Thus,
`diastolic pressure can be changed either by a volume-
`dependent change in operating stiffness or by a volume-
`independent change in chamber stiffness.
`Cardiac muscle behaves as a viscoelastic material,
`developing a resisting force (stress, ␴) as myocardial
`length is increased (strain, ␧) by ventricular filling. Strain
`is the deformation (increased length) of the muscle pro-
`duced by the application of a force (increased stress).
`Myocardial stiffness can be quantified by examination of
`the relationship between myocardial stress and strain
`during diastole. At any given strain, myocardial stiffness is
`to the slope (d␴/d␧) of a tangent drawn to the
`equal
`stress-strain relationship at that strain. Because the stress-
`strain relationship is curvilinear and exponential,
`the
`relationship between d␴/d␧ and stress is linear, and the
`slope of this relation, Km, is the modulus of myocardial
`stiffness (or myocardial stiffness constant). When myocar-
`dial stiffness is increased,
`the stress-strain relationship
`shifts to the left, so that for any given change in myocar-
`dial length (strain), there is a greater increase in force (wall
`stress) that develops to resist this deformation. In addition,
`the slope of the d␴/d␧-versus-stress relationship becomes
`steeper and Km increases when myocardial stiffness is
`increased.
`Thus, these measurements can be used to quantify changes
`in diastolic function that occur during the development of
`diastolic heart failure. These measurement techniques can
`also be used in experiments designed to identify the mecha-
`
`nisms that cause diastolic heart failure. Finally, these mea-
`surement techniques can be used to evaluate the effectiveness
`of therapeutic strategies to treat diastolic heart failure. Part 2
`of this article53 will describe the mechanisms that have thus
`far been identified as playing a causal role in the development
`of diastolic heart failure and will discuss the efforts being
`made to develop clinical therapeutic trials that target these
`mechanisms.
`
`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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