Unlocking the Mysteries of Diastolic Function · Unlocking the Mysteries of Diastolic Function ... FRCPC, FASE,* A. Jamil Tajik, MD, FACC,* Rick A. Nishimura ... Better understanding

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Journal of the American College of Cardiology Vol. 51, No. 7, 2008© 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00P

STATE-OF-THE-ART PAPER

Unlocking the Mysteries of Diastolic FunctionDeciphering the Rosetta Stone 10 Years Later

Steven J. Lester, MD, FACC, FRCPC, FASE,* A. Jamil Tajik, MD, FACC,*Rick A. Nishimura, MD, FACC,† Jae K. Oh, MD,†Bijoy K. Khandheria, MBBS, FACC, FASE, FESC,* James B. Seward, MD, FACC†

Scottsdale, Arizona; and Rochester, Minnesota

It has now been a quarter of a century since the first description by Kitabatake and his associates of the use ofecho-Doppler to characterize the transmitral flow velocity curves in various disease states. A decade ago we de-scribed the role of echocardiography in the “Evaluation of Diastolic Filling of Left Ventricle in Health and Disease:Doppler Echocardiography Is the Clinician’s Rosetta Stone.” Over the ensuing decade, advances in echo-Dopplerhave helped to further decipher the morphologic and physiological expression of cardiovascular disease and un-lock additional mysteries of diastology. The purpose of this review is to highlight the developments in echo-Doppler and refinements in our knowledge that have occurred over the past decade that enhance our under-standing of diastology. (J Am Coll Cardiol 2008;51:679–89) © 2008 by the American College of CardiologyFoundation

ublished by Elsevier Inc. doi:10.1016/j.jacc.2007.09.061

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cho-Doppler with its high spatial and unequaled temporalesolution has revolutionized our clinical access to cardiachysiology and pathophysiology. It has now been a quarterf a century since the first description by Kitabatake et al.1) of the use of echo-Doppler to characterize the transmi-ral flow velocity curves in various disease states. A decadego we described the role of echocardiography in theEvaluation of Diastolic Filling of Left Ventricle in Healthnd Disease: Doppler Echocardiography Is the Clinician’sosetta Stone” (2), the Rosetta Stone here being used as aetaphor to refer to anything that is a critical key to a

rocess of decryption or translation of a difficult problem.he term “diastology” continues to refer to the science and

rt of characterizing left ventricular (LV) relaxation, fillingynamics, and their integration into clinical practice. Thehysiology of diastole remains valid as discussed a decadego (2). However, over the ensuing decade, advances incho-Doppler have helped to further decipher the morpho-ogic and physiological expression of cardiovascular diseasend unlock additional mysteries of diastology. The purposef this review is to highlight the developments in echo-oppler and refinements in our knowledge that have

ccurred over the past decade that enhance our understand-ng of diastology. Developments include:

rom the *Division of Cardiovascular Disease, Mayo Clinic, Scottsdale, Arizona; andMayo Clinic, Rochester, Minnesota.

mManuscript received August 9, 2007; revised manuscript received September 20,

007, accepted September 24, 2007.

. Epidemiologic studies highlighting the prevalence andprognosis of those with diastolic dysfunction with andwithout clinical symptoms

. The concept of “continuity disease” and “clustering”

. Noninvasive measures of the acuity and chronicity ofLV filling pressure elevation

. Concepts of blood flow propagation within the LV

. Stress testing, diastolic function response

. The integration of echo-Doppler measures of diastolicfunction into a therapeutic treatment paradigm

. Better understanding of the relationship of myocardialform with function and the ability to characterizemeasures of myocardial mechanics

pidemiology

ver the past decade, there has been a steady rise in therevalence of heart failure in those with a preserved LVjection fraction (diastolic heart failure) (3). By the seventhecade of life, the incident cases of heart failure with areserved LV ejection fraction approach, and by the eighthecade of life exceed, those of heart failure with reduced LVjection fraction (4). The survival of patients with thelinical syndrome of heart failure is similar in those withersevered versus those with a reduced LV ejection fraction5). The understanding of diastology has become even moreermane to the practice of medicine as our understandingvolves of the profound adverse clinical consequences oflinically overt diastolic dysfunction and that the prevalencef asymptomatic diastolic dysfunction in the general com-
unity is not insignificant, a finding being noted in approx-

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680 Lester et al. JACC Vol. 51, No. 7, 2008Unlocking the Mysteries of Diastolic Function February 19, 2008:679–89

imately 25% to 30% of individu-als �45 years of age (6,7). Note,diastolic dysfunction and dia-stolic heart failure are not inter-changeable terms. Diastolic heartfailure is used to describe clini-cally symptomatic individualswith the characteristic syndromeof heart failure in the setting of anormal ejection fraction, whereasdiastolic dysfunction simply de-notes an abnormality of dia-stolic function and does notcharacterize the clinical statusof an individual.

“Continuity Disease”

The cardiovascular system is acontinuous system of reservoir,pump, and vessels. An ailment inone part of the system will influ-ence all contiguous components.An increase in vascular and ven-tricular stiffness is an integralcomponent of aging (8 –12).Vascular and ventricular stiffnessappear to be a precipitant to im-

aired cardiac performance and clinical prognosis. Vasculartiffness histologically is associated with changes in vesselall architecture and perivascular fibrosis (13). A change in

he extracellular matrix of the myocardium, with the for-ation of excess collagen tissue and serologic evidence of an

ctive fibrotic process, is a characteristic finding in thoseith diastolic dysfunction (14,15). At the cellular level,

here is reduced phosphorylation of sarcomeric proteins (16)nd at the proteomic level, an isoform change in importanttructural proteins such as titin, which functions to connectarcomeres at their ends (Z-discs) and participates in cellignaling (15,17,18). The change in cardiovascular elastances a marker for increased cardiac morbidity, and not surpris-ngly, it appears to be most prevalent in that segment of theommunity most likely to develop the clinical syndrome ofeart failure independent of the underlying LV ejectionraction (11).

Effective arterial elastance (Ea) can be estimated as theatio of end-systolic pressure/stroke volume (19). End-ystolic pressure is estimated as (0.9 � systolic bloodressure) and stroke volume the product of the left ventric-lar outflow tract (LVOT) area and LVOT time velocityntegral. During diastole, when the mitral valve is open, theeft atrium (LA) is exposed to the loading pressure withinhe LV. Over time, exposure of the LA to increased fillingressure will result in its remodeling reflected in the measuref LA volume. A simple yet robust marker for the chronicity

Abbreviationsand Acronyms

A � A velocity

ACEI � angiotensin-converting enzyme inhibitor

ARA � aldosteronereceptor antagonist

ARB � angiotensin Ireceptor antagonist

DT � deceleration time

DTI � Doppler tissueimaging

E � E velocity

Ea � arterial elastance

IVRT � isovolumicrelaxation time

LA � left atrium

LV � leftventricle/ventricular

LVOT � left ventricularoutflow tract

SRivr � strain rate duringthe isovolumic relaxationphase of the cardiac cycle

Vp � mitral inflowpropagation velocity

f change in Ea appears to be the LA size. In clinical

ractice, LA size expressed as volume indexed to bodyurface area is recommended (20,21). The biplane area-ength or Simpson’s methods are a practical means withhich to measure LA volume (Fig. 1).The LA volume can be viewed as a morphologic expres-

ion of LV diastolic dysfunction. Left atrial volume isegarded as a “barometer” of the chronicity of diastolicysfunction and to analogize, LA volume is to diastolicunction and to all forms of heart disease as the HbA1c is toiabetes. This simple measure of LA volume providesignificant insight into an individual’s risk for the develop-ent of adverse cardiovascular events including, myocardial

nfarction, stroke, atrial fibrillation, and heart failure (22–5). Left atrial volume is graded relative to risk, 28 to 33l/m2 � mild; 34 to 39 ml/m2 � moderate; and �40l/m2 � high or severe (23). For the practicing cardiologist,A volume, therefore, may be considered an excellent

Figure 1 Biplane Methods WithWhich to Calculate LA Volume

(A) Biplane area length, A1 � left atrial (LA) area, 4-chamber view; A2 � LAarea, 2-chamber view; L1 and L2: length from midplane of mitral annulus tosuperior LA, L � LA length, L1 or L2 whichever is shorter; (B) Biplane Simp-son’s where the volume of the LA is calculated as the sum of the volume ofeach individual disc.

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681JACC Vol. 51, No. 7, 2008 Lester et al.February 19, 2008:679–89 Unlocking the Mysteries of Diastolic Function

iomarker of the chronicity of diastolic dysfunction and ofardiovascular disease risk (26).

lood Flow and Myocardial Tissue Velocities

n enlarged LA reflects chronicity of LV filling pressurelevation while Doppler-derived LV filling dynamics, whicheflect acuity, can vacillate moment to moment. An inte-rative evaluation of acuity and chronicity allows for clinicaltaging of diastolic dysfunction (Fig. 2). The strengths andeaknesses of various parameters used in the evaluation ofV filling pressure are outlined in Table 1 and discussed in

he following text.The mitral inflow velocity profile is used to initially

haracterize LV filling dynamics. The E velocity (E) repre-ents the early mitral inflow velocity and is influenced by theelative pressures between the LA and LV, which, in turn,re dependent on multiple variables including LA pressure,V compliance, and the rate of LV relaxation. The Aelocity (A) represents the atrial contractile component ofitral filling and is primarily influenced by LV compliance

nd LA contractility. The deceleration time (DT) of the Eelocity is the interval from peak E to a point of intersectionf the deceleration of flow with the baseline and it correlatesith time of pressure equalization between the LA and LV

Fig. 3). As the early LA and LV filling pressures eithervolve toward or away from equivalence, so will the DTither shorten or lengthen respectively.

Diastolic dysfunction is directly related to the reductionn early LV relaxation compromising the effective transfer ofhe blood from the atrial reservoir into the LV cavity. Theeduction in LV relaxation may be characterized throughhe evaluation of mitral annular motion, generally withoppler tissue imaging, which can resolve subtle changes inV relaxation by identifying a low septal annular earlyiastolic mitral annular motion (e=) velocity (�10 cm/s).here are 2 fundamental causes of delayed LV relaxation

nd elevation of early LV filling pressure:

Figure 2 The Natural Historyof Diastolic Function and LV Filling

DD � diastolic function; e= � early diastolic mitralannular velocity; LAP � left atrial pressure; LV � left ventricular.

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. The LV chamber is distorted (e.g., infarction, hypertro-phy, cardiomyopathy, and dyssynergic wall motion),impairing the effective transfer of blood from the mitralorifice to the LV apex.

. The LV ejection period is prolonged due to increasedventricular-arterial afterload.

ncomplete or delayed relaxation causes a delay in theransfer of blood from atria to ventricle. The pressuresmpeding forward flow are reflected backward (continuity

trengths and Weaknesses of the Parameterssed in the Evaluation of LV Filling Pressure

Table 1 Strengths and Weaknesses of the ParametersUsed in the Evaluation of LV Filling Pressure

Strengths Weaknesses

PW mital inflow 1. Can be obtainedin nearly all patients

2. Diagnostic andprognostic information

1. Highly pre-loaddependent

2. Quantitative valuesinfluenced by PW samplevolume placement

3. Problematic at high heartrates, atrial fibrillation,heart block, pacedrhythms

4. Measurement of DTwhen there is a nonlinearvelocity decline

DTI (e=) 1. Can be obtained inmost patients

2. Early marker ofdiastolic dysfunction

3. Not influenced bychanges in heart rate

4. Primarily loadindependent in diseasestates

1. Influenced by localchanges in wall motion(infarction)

2. Possible influence bypericardial adhesions(note, possible strengthtoo in helping todifferentiate constrictionfrom restriction)

PV flow 1. The relationship ofPVAR to mitral Aduration is the onlymarker specific forelevation in LVEDP

2. Complements PWmitral inflow andparticularly helpfulwhen there is E- andA-wave fusion to helpclassify diastolic filling

1. Can be difficult to obtainadequate signals

2. Influence by changes inrhythm (atrial fibrillation)

Mitral inflowpropagation

1. Provides temporal,velocity, and spatialinformation

1. Observer reproducibility2. Dependent on pre-load

and cardiac chamber size

IVRT 1. Represents the earliestphase of diastole

1. Requires defining timingof 2 separate events AVCand MVO that may needslightly different imagingplanes

2. Measurementreproducibility

LA volume 1. Provides morphologicand physiologicalevidence for chronicelevation in fillingpressure

2. Severity scale based onclinical outcomes

1. Chronic volume overload(e.g., anemia, athleticheart, compensatedvalve disease) can resultin an increase in LAvolume yet a normal LVfilling pressure

VC � aortic valve closure; DT � mitral E-wave deceleration time; DTI � Doppler tissue imaging;= � septal annular early diastolic tissue velocity; IVRT � isovolumic relaxation time; LA � lefttrial; LV � left ventricular; LVEDP � left ventricular end-diastolic pressure; MVO � mitral valvepening; PV � pulmonary vein; PVAR � pulmonary vein A reversal duration; PW � pulsed wave.

isease) into the atria and pulmonary veins. Early in the

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volution of “diastolic dysfunction” the delay in emptyingDT �240 ms) is partially compensated by a more vigorousnd-diastolic atria contraction, and, hence, the E/A ratio iseduced (�0.9, grade I diastolic dysfunction). With furtherncreased impedance to atrial emptying, atrial pressurencreases, and the relative difference between atria andentricular pressure decreases (DT shortens). As a result,he E velocity and E/A ratio will now increase, and theitral inflow velocity profile may appear normal (E/A � 0.9

o 1.5 and DT � 160 to 240, grade II diastolic dysfunction).owever, the e= velocity will remain reduced, identifying

he underlying LV relaxation abnormality. A reduced e=elocity, increased E/e= ratio, and associated increased LAolume (�28 ml/m2) can, therefore, be readily used toiscriminate an individual with normal versus grade IIpseudonormal) diastolic dysfunction (27,28). Similarly,ndividuals with grade III diastolic dysfunction, E/A �2,nd DT �160 ms who are able to favorably influence theiritral inflow velocity profile with hemodynamic manipula-

ion, often the Valsalva maneuver, declare themselves of lessevere diastolic dysfunction than those with grade IViastolic dysfunction who have an irreversible restrictiveattern and a very poor prognosis.Insights into LV diastolic function can be deciphered

hrough the evaluation not only of the relationship of themplitude of E to e= but also through the evaluation of theelationship of the timing of the onset of E to the onset of=. Normally mitral inflow is initiated with rapid LVelaxation and “suction” of blood into the LV. When thisccurs, the onset of e= will be slightly before or simultaneousith the onset of E. If, however, LA pressure is elevated andV relaxation reduced, E velocity onset may precede thenset of e=. These timing relationships have been correlatedith LV filling pressure (29,30) (Fig. 4).A limitation of the use of the e= velocity is the fact that

Figure 3 The Mitral Inflow Velocity Profile

A � atrial component of mitral filling;DT � deceleration time; E � early diastolic mitral inflow velocity.

cquisition is generally from a single site, the mitral annulus,

nd values obtained assume that they reflect global LVelaxation. Although much less practical, the average e=elocity from multiple sites enhances the test characteristicsf the E/e= ratio to predict LV filling pressures (31). The usef 2-dimensional speckle tracking technologies allows forhe characterization of global parameters of myocardialotion. A measure of global diastolic strain rate during the

sovolumic relaxation phase of the cardiac cycle (SRivr)irectly measures a global myocardial relaxation parameter

ess influenced by annular and valvular pathology. Theelationship of the mitral E-wave velocity to SRivr appearso provide enhanced discriminatory power with which toetect an elevation in mean pulmonary capillary wedgeressure when compared with the E/e= ratio (Fig. 5) (32).ulmonary vein flow. The ability to evaluate myocardialotion with high temporal resolution (Doppler tissue

maging) and thus detect the underlying LV relaxationbnormality (low e=) present with little exception in thoseith diastolic dysfunction has minimized, but not relegatedbsolete, the utility of the evaluation of pulmonary vein flown the assessment of LV filling pressure. Over the pastecade, insights into the physiology of the pulmonary veinoppler velocity profile has evolved (33). The parameterseasured and insights into diastolic function gained from

heir interpretation, however, remain as discussed a decadego (2). It is worthy of note that if the mitral inflow velocity

Figure 4 Transmitral Doppler andTissue Doppler of the Mitral Annulus

(A) Normal left ventricular filling pressure. (Left) Mitral inflow velocity profile;(right) septal annular tissue velocity profile. (B) Elevated left ventricular fillingpressure. e= � early diastolic mitral annular velocity; other abbreviations as inFigure 3.

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rofile indicates a predominant relaxation abnormality withlow E/e= ratio (normal mean LA pressure), a pulmonary

ein flow duration greater than mitral inflow duration attrial contraction may indicate an earlier stage of reducedV compliance as well as increased LV end-diastolicressure.sovolumic relaxation time (IVRT). The IVRT is theime interval between aortic valve closure and mitral valvepening. The transducer is placed in the apical position withither a pulsed or continuous wave Doppler sample placedetween the aortic and mitral valves. A normal IVRT ispproximately 70 to 90 ms. The IVRT will lengthen withmpaired LV relaxation and shorten when LV compliance isecreased and LV filling pressures are increased. Note theVRT will vary with heart rate and ventricular function,nd, thus, absolute values cannot always be interpreted toichotomize normal versus abnormal LV filling pressure.sovolumic relaxation time may be very helpful in followinglinical response to various treatment strategies.

itral inflow propagation velocity (Vp). Important in theechanics of LV diastole are regional differences in myo-

ardial relaxation. Normally there is a wave of relaxationriginating at the apex and moving toward the base. Thisesults in a base-to-apex pressure gradient allowing blood toiterally be sucked into the LV. With LV diastolic dysfunc-ion and the associated relaxation abnormality, the regional

Figure 5 Global Strain Rate Profile

Global strain rate (SR) signal (purple, right axis), and mitral velocity (left axis)tracings by color tissue Doppler from the septal (blue) and lateral side (red) ofthe mitral annulus from the same cardiac cycle. Note the SR signal during theisovolumic relaxation phase of the cardiac cycle (*) and the correspondingvelocity tracings from the mitral annulus recording during the same interval. Aa� late diastolic velocity; AVC � aortic valve closure; Ea � mitral annulus earlydiastolic velocity; GSRa � global strain rate during late left ventricular filling;GSRe � global strain rate during early left ventricular filling; GSRivr � globalstrain rate during the isovolumic relaxation phase of the cardiac cycle period;MVO � mitral valve opening. Reprinted, with permission, from Wang et al. (32).

ifferences in relaxation are less pronounced and the intra-

entricular pressure gradient responsible for normal LVlling reduced or even absent.Color M-mode of the mitral inflow obtained by placing

he M-mode cursor in the direction of the mitral inflow jeteen on the color Doppler map can be used to evaluate LVelaxation (34–36). This display will provide temporal,patial, and velocity information. There have been variousethods described with which to calculate the Vp from LV

ase (annulus) to apex. A practical approach is to measurehe slope of the line of the first aliasing velocity from theitral valve plane to approximately 4 cm distal into the LV

normal �50 cm/s) (Fig. 6). Like e=, Vp characterizes LVelaxation, and not surprising, therefore, the ratio of E/Vpan be used to estimate LV filling pressure, with an E/Vp1.5 suggestive of a pulmonary capillary wedge pressure of15 mm Hg (37,38). Caution in the interpretation of this

atio is recommended in the setting of LV hypertrophy andsmall LV cavity size where Vp may be high and this ratioay not, therefore, accurately reflect LV filling pressure. In

ur clinical practice, we perform only a qualitative interpre-ation of the color M-mode mitral inflow velocity onlyroviding an estimate of the velocity, temporal, and spatialistribution of LV filling.

ractical Approach

lthough there are other echocardiographic parameters thatay be used to characterize diastology, the parameters

iscussed in the preceding text represent those that areommonly used in daily practice. The measure of LAolume is the cornerstone to evaluation for its ability torovide insight into the chronicity of elevation of LV fillingressure and to characterize global cardiovascular risk.Initial observations of 2-dimensional echocardiographic

eatures often provide diagnostic clues as to the status ofiastolic function. Patients with diastolic dysfunction qual-

Figure 6 Mitral Inflow Propagation Velocity

bpm � beats/min; HR � heart rate.

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tatively may have increased LV wall thickness, an increasen LA size, and reduced mitral annular motion. The moreuantitative assessment of diastolic function and the “acuity”easure of LV filling pressure then generally begins by

haracterizing the mitral inflow velocity profile as eitherormal (E/A ratio 0.9 to 1.5, DT 160 to 240 ms), restrictiveE/A ratio typically �2, DT �160 ms), or delayed relax-tion (E/A ratio �0.9, DT �240 ms). A dilemma existshen the mitral inflow velocity profile is characterized asormal and the integration of the measures of mitral inflowith measures of tissue and other blood flow velocities help

o decipher normal from abnormal diastolic function (Table). The E/SRivr is an intellectually intriguing parameterhat with further validation may become standard in thevaluation of LV filling pressures.

Although particular reference is made to the septal mitralnnular e= velocity, the lateral mitral annular e= velocity maylso be useful. It must be noted, however, that the lateral e=elocity generally exceeds the septal e= velocity, and, thus, inur practice a lower E/e= cutoff (12 vs. 15) is used toichotomize normal from elevated filling pressures when the

ateral e= velocity is used. The E/e= ratio derived from theeptal e= is preferred (28).

When the mitral inflow velocity profile is characterized asestrictive, it too is important to integrate these findingsith measures of mitral annular motion as discussed in thereceding text. With rapid relaxation (health), the LV isble to “suck” blood into itself at high velocities and the E/Aatio may exceed 2. Here, however, the rapid relaxation islearly denoted by a robust annular e= velocity and low E/e=atio. One important clinical caveat is constrictive pericar-itis, where the e= velocity may be normal and the E/e= ratio

ow despite an increase in LV filling pressure (“annulusaradoxus”) (39). A low e= and increase in E/e= ratio

etermination of Diastolic Function Grade

Table 2 Determination of Diastolic Function Grade

Normal

PW-mitral inflow

DT (ms)* 160–240

E/A* 0.9–1.5

Modifiers DTI*

e= (cm/s) �10

E/e= (septal) 1–14

LAVI* (ml/m2) 22 � 6

Valsalva Negative

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Mitral inflow propagation

Vp (cm/s) �50

E/Vp �1.5

Most important.
E/A � the ratio of the mitral early (E) and atrial (A) components of the mitral inflow velocity profile; LAVI �
ein second systolic forward flow velocity; Valsalva positive � E/A ratio to decrease by �0.5 and increas

onfirms a reduction in LV diastolic function and anncrease in LV filling pressure.

A non–E-wave dominant mitral inflow velocity profilessentially excludes demonstrable increases in LV fillingressure. However, here too a measure of LA volume and e=s important, as there is a subset of individuals with a mitralnflow velocity profile characterizing a relaxation abnormal-ty (grade I) diastolic dysfunction who have an increased LAolume and/or an increased septal E/e= ratio (�15, e.g., E

80 cm/s, A � 110 cm/s, e= � 4 cm/s, E/e= � 20). Weesignate these individuals as having grade Ia diastolicysfunction (mild elevation in LV filling pressure).

iastolic Stress Test

patient reporting symptoms of dyspnea in the setting of aormal pulmonary evaluation, a negative contemporarytress test, and normal resting diastolic function oftenresents a clinical enigma. Analogous to those with reactiveirways disease, diastolic dysfunction my not be identifiedithout provocation, “diastolic stress test.” The mitral

nnular e= velocity is not significantly altered by changes inardiac cycle length. Any change in e= velocity notedecondary to a change in cardiac cycle length is directlyelated to the transmitral pressure gradient as thus concor-ant changes in the mitral E-wave velocity are noted (40).he E/e= ratio is a representation of mean LA pressure and

an be measured during an echocardiographic stress test41,42). Mean LA pressure with exercise remains withinormal limits in healthy individuals. Therefore, a measuref the E/e= ratio during aerobic stress may be useful foristinguishing patients with cardiac disease and help toolve the clinical enigma (41–44).

de 1)

Moderate(Grade 2)

Severe(Grade 3)

Severe(Grade 4)

0 160–240 �160 �130

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reatment

n clinical medicine there are essentially only 2 therapeuticargets: to improve symptoms and, hence, quality of life, ando enhance survival, quantity of life. In those with thelinical syndrome of heart failure, it must be emphasizedhat heart failure is not a diagnosis but rather a constellationf signs and symptoms representing a final common path-ay of a heterogeneous group of diseases (45). In thoseresenting with the clinical syndrome of heart failure, oneust initiate a meticulous search for the underlying etiology

nd precipitant causes. As such, the treatment strategy muste first and foremost directed toward the identification andorrection of the underlying precipitating and pathogenicechanism(s) (Table 3). This highlights the need to indi-

idualize the therapeutic approach.ondisease-specific (general) therapeutic approach. Gen-

ral, nondisease-specific therapies are then used to helpetter control symptoms. These therapies may too beailored to an outcome of a more favorable diastolic functionrade (Fig. 2). In the normal heart, as heart rate increaseshere is an increase in contractility and faster relaxation. Inyocardial disease, there is a slower LV pressure decline

nd incomplete pressure restitution, and thus higher LViastolic pressure and reduced coronary flow reserve. For

ndividuals with grade I and II diastolic dysfunction, theuration of diastole is critical, and beta-blockers or rate-lowing calcium-channel blockers often provide a favorableymptomatic response allowing more time for ailing diastoleo do its work either at rest and/or to truncate an exercise-nduced increase in heart rate. In contrast, in patients withrade III or IV diastolic dysfunction, LV filling may beomplete by mid-diastole. Such patients have a fixed strokeolume, and empirically slowing the heart rate into the 50snd 60s may result in a further reduction in cardiac outputnd a worsening of the clinical symptom complex. There-

ommon Etiologies of Diastolic Heart Failure

Table 3 Common Etiologies of Diastolic Heart Failure

Etiology of DiastolicHeart Failure Management

Systemic hypertension Adequate control and monitoring of bloodpressure

Ischemic heart disease Relieve ischemic (acute or chronic)

Diabetic heart disease Good blood sugar control

Obesity/metabolic syndrome Reduce weight, lipid management

Sleep-disordered breathing CPAP

Valvular heart disease Early intervention

Constrictive pericarditis Pericardiectomy

Restrictive cardiomyopathy Symptomatic treatment, cardiac transplant

Hypertrophic cardiomyopathy Pharmacotherapy, relieve outflow obstruction

Infiltrative disorders(e.g., amyloid)

(e.g., stem cell transplant)/disease-specifictreatment

Storage disease(e.g., hemachromatosis)

(e.g., phlebotomies)/disease-specifictreatment

PAP � continuous positive airway pressure.

ore, in these patients, the initiation of beta-blocker therapy

hould be monitored closely and initiated with small dosesith small increments.Diuretics have a salutary effect on symptoms by reducing

ntravascular volume and steering the LV to a more favor-ble position on its end-diastolic pressure volume relationnd reducing pericardial restraint (Fig. 7). Therapies thatesult simply in a change in position on the LV end-iastolic pressure volume curve without imparting a rightnd downward curve shift are likely analogous to treating aever with acetaminophen; they improve the symptom buto not influence the underlying root cause and, hence, haveo impact on long-term survival. Those able to respondavorably to hemodynamic manipulation do, however, ap-ear to have a better prognosis (46–48) as they likelyepresent those with less severe disease. Intriguing areherapies that may favorably influence the underlying finalommon pathway, the increase in vascular and ventriculartiffness.reating the final common pathway, vascular-ventricular

tiffness. The presence of diastolic dysfunction regardlessf symptom status portends significant risk for futuredverse cardiovascular outcomes, and the absence of patientoiced complaints does not support the absence of thera-eutic intervention. In those with clinically occult diastolicysfunction, the initial therapeutic approach is identical tohat recommended for those with symptoms: identify andreat the underlying etiology and precipitant cause(s). Forxample, the treatment of hypertension in those withlinically occult diastolic dysfunction results in an objectivemprovement in diastolic function (49). Neurohormonal

odulation of the renin-angiotensin-aldosterone systems currently the only therapy with a salutary effect onome of the pathophysiological mechanisms responsible forhe increase in vascular and ventricular stiffness (50,51).

Figure 7 The LVEDP Volume Relationship

Purple � more favorable position; Green � less favorable position.LV � left ventricular; LVEDP � left ventricular end-diastolic pressure.

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ngiotensin-converting enzyme inhibitors (ACEIs), angio-ensin I receptor antagonists (ARBs), and aldosterone re-eptor antagonists (ARAs), independent of their hemody-amic effects, mediate potentially favorable effects ofeduced smooth muscle cell growth, prevention of collageneposition, reduced growth factor expression, and regres-ion of myocardial fibrosis (52–56). The finding of annlarged LA in the absence of a definitive underlyingrecipitating cause (e.g., mitral regurgitation or a highutput state) is a call to arms, and our approach beyondherapeutic lifestyle intervention is to initiate ACEI or ARBherapy currently targeting a blood pressure of 110/75 mm

g. Of interest, ACEI therapy may result in favorableemodeling of the LA independent of their influence onlood pressure (57).In those with the clinical syndrome of heart failure and a

reserved LV ejection fraction, an evidence-based approacho treatment is lacking; however, there is informationupporting a clinical judgment-based approach to manage-ent. The CHARM-Preserved (Effects of Candesartan inatients With Chronic Heart Failure and Preserved Left-entricular Ejection Fraction) trial, a prospective outcome

rial evaluating a treatment strategy (candesartan) solely forndividuals with heart failure and a normal ejection fraction,ncluded a heterogeneous etiologic classification of heartailure (58). The findings, however, were promising, show-ng a significant reduction in hospitalization for heart failurend a strong trend toward significance in the primaryutcome of death or hospital admission for heart failure.he PEP-CHF (Perindopril in Elderly People withhronic Heart Failure) study evaluated individuals �70

ears of age with a clinical diagnosis of heart failure and areserved LV ejection fraction. Here too the findings wereromising, showing an improvement in symptoms andxercise capacity along with fewer hospitalizations in thosen the active treatment group noted in the first year ofollow-up (59). We await the results of the I-PRESERVEIrbesartan in Heart Failure with Preserved Systolic Func-ion) trial, where inclusion defined a more discriminateatient population (60).Statins similarly have touted favorable pleiotropic effects

oo on diastolic function, and the art of medicine suggestshat a low threshold for the use of statins may be appropriate61,62). Beta-blockers as discussed in the preceding text areften helpful in the symptomatic management of patientsith diastolic heart failure. However, several clinical trials,

gain including individuals with heterogeneous pathophys-ological mechanisms for heart failure, have shown thatrimarily those with too low an LV ejection fraction mayerive a survival advantage with beta-blocker therapy63,64). The SENIORS (Study of the Effects of Nebivololntervention on Outcomes and Rehospitalisation in Seniorsith Heart Failure) trial suggests that the elderly with heart

ailure can tolerate beta-blocker therapy and derive a favor-ble clinical benefit (reduction is composite of death or
ardiovascular hospitalization) particularly if target doses are p
chieved (65). This trial did include patients with preservedV ejection fractions (approximately one-third), but theean LV ejection fraction for each group was approximately

5%. Other trials have suggested that the use of beta-lockers in those with heart failure and a preserved LVjection provides mortality benefit (66).

Endothelin influences myocardial inotropic and lusiotro-ic function, and intellectually intriguing is the potentialole of an endothelin receptor antagonist in the manage-ent of patients with heart failure (67,68). However, when

valuated in an etiologically heterogeneous group of heartailure patients, endothelin receptor blockers when added totandard therapy did not improve outcome, currently cast-ng doubt on the use of endothelin receptor blockers for the

anagement of heart failure (69–71). Further pathophysi-logical insight into disease inception may influence novelherapeutic strategies targeting the vasculature, with endoints encoded somewhere in the cardiovascular structuralnd functional continuum. For example, it has recently beenroposed that endothelial cells may, in fact, transition intoesenchymal cells and thus contribute fibroblasts to the

rocess of cardiac fibrosis (72). In a mouse model of pressureverload and chronic allograft rejection, recombinant hu-an bone morphogenic protein-7 could preserve the endo-

helial phenotype and retard the progression of fibrosis (72).n addition, preliminary small animal studies suggest thathosphodiesterase-5A inhibition with oral sildenafil mayuppress chamber and myocyte hypertrophy, remodeling,nd fibrosis by deactivating various hypertrophy signalingathways (73,74). Additional preliminary and novel strate-ies directed at influencing the final common pathway ofisease hold promise (75). Definitive comments on the

mpact of beta-blockers, ACEIs, ARBs, ARAs, statins, andther pharmacologic therapies in those with heart failurend a preserved LV ejection fraction are pending prospec-ive randomized clinical trials. Until then, such individual-zed treatments encompass clinical judgment-based thera-eutic strategies.

here Are We Going?

lthough it is practical to classify cardiac dysfunction asither systolic or diastolic, such a classification is based onhysiological principles destitute of virtue as each compo-ent of the cardiac cycle is functionally dependent on thether. Different than 2-dimensional echocardiography,here crude parameters of cardiac performance such as

jection fraction are used, Doppler echocardiography is ableo detect and quantitatively display minor amplitude andemporal subtleties that may occur in ventricular mechanicalunction. Traditionally, parameters of diastolic functionave been derived from Doppler and those of systolicunction from 2-dimensional variables. This may create thellusion that individuals have “isolated diastolic dysfunc-ion.” The interrogation of cardiac function with derived
arameters of deformation such as strain and strain rate

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onfirm the illusion despite frequent pronouncement. Mea-ures of global parameters of myocardial motion usingdvanced speckle tracking algorithms may allow for en-anced prediction models of LV filling pressure.The contemporary belief is that the macro architecture of

V myofiber geometry is chiral with the subendocardialayer composed in the form of a right-handed helix gradu-lly evolving into a left-handed helical fiber orientation inhe subepicardial layer. As such, LV fiber orientation is aunction of transmural location, with the fiber directioneing predominantly longitudinal in the endocardial andpicardial surfaces and with the helical angle changingontinuously between the endocardium and epicardium,uch that the midwall fibers have a circumferential orienta-ion forming a sort of equator of the heart (76–78). As withontraction, the endocardial and epicardial onset of relax-tion is temporally discrete beginning in the apical suben-ocardium just before closure of the aortic valve withubepicardial relaxation beginning at the base after aorticalve closure (79). Different from contraction, however,elaxation of the helixes is in the opposite direction, apex toase for subendocardium and base to apex for subepicar-ium. The temporal and spatial differences in LV relaxationre critical for the creation of forces required for diastolicuction (79). Because of the intrinsic spiral geometry of theV myofibers, shortening and lengthening of the myocar-ial wall results in rotary movements. The counter-irectional rotation of the LV apex with respect to the base

s referred to as LV twist or torsion. By convention, rotations described from the apical end of the LV, with clockwisend counterclockwise rotations shown in negative andositive degrees, respectively (Fig. 8). Our now betternderstanding of myocardial form and myofiber architec-ure paralleled with advances in ultrasound signal processingave allowed the subtleties of myocardial motion to beharacterized and quantified (80).

Figure 8 VVI Illustrating the Rotation Motion of the LV Apex

(Left) Systole where the apical rotation is predominantly anticlockwise; (right)systole where the apical rotation (now untwisting) is predominantly in the clock-wise direction. LV � left ventricular; VVI � Velocity Vector Image.

In the end, the heart is simply a pump, albeit a complexnd sophisticated one that serves to deliver blood to theody. Although we can now begin to decipher the complexotion needed to complete this task, intriguing are tech-

iques that can also decipher the complexities of the finalommon purpose of cardiac pump function, blood flow (81).erhaps systolic and diastolic dysfunction will no longer beiewed clinically as dichotomous terms but rather voiced asust “cardiac dysfunction.” The echocardiography laboratoryill evolve into a cardiovascular physiology and pathophys-

ology laboratory able to decipher the subtle morphologicnd physiological characteristics of a heterogeneous groupf cardiovascular diseases (82). We will then be able tovolve a new paradigm of what we define as “disease” withechophysiology” providing insights allowing for more ac-ive intervention for prevention strategies. Perhaps in an-ther decade all inscriptions on the Rosetta Stone will beeciphered and we will realize that the translation was not

ust that of diastology but rather cardiovascular physiologynd pathophysiology. Until then. . .

eprint requests and correspondence: Dr. Steven J. Lester,ardiovascular Diseases, Mayo Clinic Arizona, 13400 East Sheaoulevard, Scottsdale, Arizona 85259. E-mail: [email protected].

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Unlocking the Mysteries of Diastolic Function · Unlocking the Mysteries of Diastolic Function ... FRCPC, FASE,* A. Jamil Tajik, MD, FACC,* Rick A. Nishimura ... Better understanding