Assessment of Diastolic Function

ones Miguel A. Quin

ultiple factors contribute to normal diastolic filling at rest and with exercise. They include myocardial relaxation, left atrial pressure or preload, the overall compliance or stiffness of the left ventricular (LV) chamber, and atrial contraction. Chamber stiffness is determined by myocardial stiffness, the geometry of the left ventricle, pericardial constraint, and ventricular interdependence. Myocardial relaxation and chamber stiffness provide the left ventricle with the ability to fill rapidly while maintaining normal diastolic pressures at rest and during exercise. Myocardial diseases that result in diastolic dysfunction universally affect both relaxation and chamber stiffness, and result in the need to recruit higher left atrial (LA) pressures to maintain filling at rest or with exertion. An effective atrial contraction is not only necessary to boost LV filling during exercise but in patients with diastolic dysfunction, it becomes an essential compensatory mechanism to enhance LV filling and maintain normal mean LA pressures (LAPs). However, because all cardiac diseases do not alter relaxation and stiffness to the same degree, a wide range of clinical presentations and diagnostic findings are seen from one patient to another. Ideally, one would like to have accurate and widely available techniques to measure myocardial relaxation and chamber stiffness. To date, however, all available methods have limitations.

Invasive Methods
Myocardial relaxation is an active process that is itself directly affected by the inotropic state of the
From the Section of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, and Methodist DeBakey Heart Center, Houston, TX. Address reprint requests to Miguel A. Quin ones, MD, FACC, Section of Cardiology, Department of Medicine, Baylor College of Medicine, 6550 Fannin St, Suite 1901, Houston, TX 77030. 0033-0620/$ - see front matter n 2005 Published by Elsevier Inc. doi:10.1016/j.pcad.2005.02.009

myocardium and inversely by aging, disease states, and afterload. To date, the most accurate clinical assessment of relaxation is obtained by recording LV pressures with catheter-tip highfidelity micromanometers and measuring any of the following parameters: peak () dP /dt , the time-constant of relaxation (Tau ), and the lowest early diastolic pressure.1,2 Although considered by many experts as bgold standards,Q these measurements are clinically cumbersome to obtain and require the use of expensive catheters. Furthermore, because of their limited use, there are no large-scale clinical studies defining the normal ranges for these measurements in normal subjects over a wide age range or with different disease states. Thus, they are reserved for research investigations and have limited clinical use. Chamber stiffness is defined by the diastolic LV pressurevolume relation and has been discussed in detail elsewhere in this issue. Although useful for conceptual evaluation of diastolic dysfunction, these curves are extremely cumbersome to derive and are of limited clinical use. Furthermore, the ultimate effect of increased chamber stiffness is an elevation of diastolic LV pressures. As intracardiac pressures are more readily available during heart catheterization, left ventricular end-diastolic pressure (LVEDP) is used as a surrogate for end-diastolic stiffness. However, from the patients perspective the mean pulmonary capillary wedge pressure (PCWP), used as a surrogate for mean LAP, is more important than LVEDP as it is the pressure that ultimately leads to dyspnea and pulmonary edema. The LV pressure before atrial contraction can also be used as a substitute for mean LAP.3 In the absence of acute volume loading, an elevation in any of these pressures (also referred to as filling pressures) is a specific marker of abnormal diastolic filling. However, elevated filling pressures alone do not provide much insight into the mechanisms responsible for the diastolic dysfunction. Furthermore, it is often difficult if not impossible to perform invasive evaluation at the time of clinical presentation. Nevertheless, if the procedure is to be performed

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Progress in Cardiovascular Diseases, Vol. 47, No. 5 (March/April), 2005: pp 340-355

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with echo-Doppler evidence of elevated filling pressures had an enlarged LA (unpublished observation). Thus, in our experience when patients present with dyspnea and have normal LV size, no hypertrophy, normal EF, and normal LA size, it is very unlikely that they are suffering from diastolic heart failure.

it is essential that the pressures be measured before angiography to eliminate the effect of acute volume loading.

Radionuclide Angiography
Normalized peak filling rate (NPFR) became a popular index 2 decades ago with the use of radionuclide angiography. Normalized peak filling rate is derived from the LV time-activity curve as the slope of the early diastolic rise normalized for the end-diastolic counts (as a surrogate for end-diastolic volume) and is a noninvasive index of LV relaxation. Reductions in NPFR have been observed in hypertensive patients with LVH, during exercise-induced ischemia and even at rest in patients with significant coronary artery disease.4-6 Although NPFR represents a noninvasive assessment of diastolic performance, it does not provide any estimate of filling pressures and/or LV stiffness, and is limited by its sensitivity to loading conditions.7 With the increasing use of myocardial perfusion imaging and echocardiography, radionuclide angiography has fallen into disuse.

Doppler Echocardiography Transmitral Velocity

With the advent of Doppler echocardiography, recordings of the transmitral velocity from the apical window using pulsed-wave (PW) Doppler provide a simple noninvasive approach to the evaluation of diastole. The early (E) transmitral velocity recorded at the tips of the mitral valve and its deceleration time (DT), the atrial (A) velocity, and the E/A ratio have become popular indices of diastolic function (Fig 1). The E/A ratio is a normalized index that reflects early diastolic filling relative to atrial contraction. Isovolumic relaxation time (IVRT) is the time interval between the closure of the aortic valve and the opening of the mitral. Isovolumic relaxation time is obtained by recording velocities from an intermediate position between mitral inflow and LV outflow (Fig 1). The transmitral velocity is driven by 2 major factors: flow and the instantaneous transvalvular pressure gradient.7 In young healthy hearts, the rapid relaxation of the myocardium results in a rapid decline of LV pressure during isovolumic relaxation and a shortening of IVRT (b90 milliseconds). This fast pressure drop generates a suction effect and a transvalvular gradient that promote rapid ventricular filling, resulting in a relative increase in E velocity (E/A N1.5) and shortened DT (b220 milliseconds) (Fig 1). As myocardial relaxation falls in response to aging, increased afterload, ischemia, or myocardial disease, the rate of LV pressure decline falls (ie, lower [] dP /dt , longer Tau , and higher early diastolic pressure) and the bsuctionQ effect is lessened. These changes result in prolongation of IVRT, reduction in E velocity, lengthening of DT, and a compensatory increase in A velocity (ie, E/A b1.0) (Fig 2). The transmitral velocity pattern characteristic of impaired LV relaxation has been referred to in

Two-dimensional Echocardiography
Echocardiography plays a pivotal role in the evaluation of patients presenting with symptoms and signs of heart failure. Assessment of LV size, regional wall motion, and ejection fraction (EF) is readily obtained with 2-dimensional echocardiography (2D echo) and is commonly used to separate patients into systolic and diastolic heart failure; the former being characterized by LV dilatation and depressed EF, and the latter by absence of LV dilatation and preservation of EF (z50%). In addition, 2D echo allows recognition of concentric LV hypertrophy or remodeling (a common finding in hypertensive patients with diastolic heart failure), and assessment of left atrial enlargement, an extremely frequent finding in diastolic heart failure. Although the anteroposterior LA dimension has been used for decades to determine LA size, a more accurate assessment is obtained by using either the area or volume of the LA derived from the apical views.8,9 In our experience at the Methodist DeBakey Heart Center, over the past year, 95% of 2546 patients

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A
E A

B
IVRT

C
S D

A
Fig 1. Illustration of a transmitral velocity (panel A), isovolumic relaxation (IVRT; panel B), and PVV (panel C).

the literature as type I diastolic dysfunction10 and has been observed in patients with systemic hypertension (even in the absence of hypertrophy), pathological LV hypertrophy (in contrast to hypertrophy of the athlete), ischemic heart disease, and in dilated, infiltrative, or hypertro-

phic cardiomyopathy, but also in normal elderly subjects.11-15 Although not always, this pattern is often associated with normal resting mean LAP, particularly in patients with depressed LVEF (b40%).16 Patients with type I diastolic dysfunction are more prone to develop exercise-

mmHg

cm/s

Normal

Relax.

Relax. With High LAP

Fig 2. Relation of transmitral velocity to the pressure gradient between LA and LV in 3 common hemodynamic conditions: normal relaxation, impaired relaxation (A relax.), and impaired relaxation with high LA pressure.

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short DT (b150 milliseconds). This pattern has been called brestrictive fillingQ and more recently referred to as type III diastolic dysfunction (Figs 2 and 3).10 In animal studies, DT has been shown to relate well with LV chamber stiffness in hearts with depressed EF.20 Likewise, in patients with ischemic cardiomyopathy, our laboratory has shown an inverse relation between DT and the amount of scarring detected by thallium-201 scintigraphy in the left ventricle.21 The progression from type I diastolic dysfunction to types II and III is a b2-way street,Q meaning that patients may decompensate into the advanced types and with proper treatment regress to type I. Application of the Valsalva maneuver can be used to assess reversibility as the increased intrathoracic pressure during the maneuver causes a decrease in preload and a shift in the transmitral velocity from type III to type II or from II to I.22 Type IV diastolic dysfunction is defined as a restrictive pattern that fails to reverse with either Valsalva or heart failure therapy. In patients with systolic heart failure, this pattern is associated with a poor prognosis.23,24 The transmitral velocity and IVRT are very useful in estimating mean LAP (or PCWP) in patients with depressed LVEF (b40%). A gross

induced dyspnea and are at risk for developing heart failure over time, particularly the group with dilated LA.17,18 These patients often have auscultatory evidence of a fourth heart sound and may have a prominent A wave in the LV pressure tracing. The transmitral velocity is also altered by increases (acute or chronic) in ventricular chamber stiffness and LAP.19,20 The elevated v wave in the LA results in an increase in the LV-LA crossover pressure, shortening of IVRT, and an increase in the LA-LV transmitral gradient during early diastole (Fig 2). This results in a higher E velocity, a shortened DT, and a lower A velocity (E/A N1.0), the latter occurring in response to the high LV pressure in late diastole imposing a greater afterload to the contracting atrium. This pattern resembles the one seen with normal relaxation and thus has been called bpseudonormal,Q and more recently referred to as type II diastolic dysfunction (Fig 3).10 Importantly, in patients with underlying cardiac diseases, this pattern represents a progression of disease and is always accompanied by abnormal relaxation. With further worsening of LV stiffness and higher LAPs, the transmitral velocity appears bsuper normalQ with a much higher E/A ratio (N2.0) and/or a very

Normal E A

Impaired Relaxation Type I A E

Pseudo-normal Type II E A

Restrictive Type III E

E/A >1 DT 150-220 IVRT <90ms

E/A < 1 DT >250 IVRT >90ms

E/A 1-1.5 DT 150-220 IVRT <90ms

E/A >2 DT <150 IVRT <70ms

Fig 3. Comparison of the normal transmitral velocity with the 3 types of diastolic dysfunction patterns. Range of values are listed under each pattern.

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mean PCWP = 17 + 5.3EA - 0.11IVRT B

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A
Doppler (mmHg)

Catheter Pressure (mmHg)

Fig 4. Correlation of mean PCWP estimated by Doppler using the above equation with PCWP by catheter (panel A). Panel B illustrates the change in mean PCWP with therapy estimated by Doppler vs catheter measurement. (Adapted from Ref. 16 ).

estimate can be given from the patterns shown in Fig 3. In addition, several equations have been proposed in the literature to derive mean PCWP.16,25-27 We have found that the equation, mean PCWP = 17 + (5 E/A) (0.11 IVRT), is simple to use and provides accurate estimates of mean PCWP in patients with depressed EF (Fig 4).16 The transmitral velocity and the IVRT

lose accuracy in the setting of diastolic heart failure with preserved LVEF. This will be discussed in more detail below.

Pulmonary Vein Velocity

Recordings of pulmonary vein velocity (PVV) by PW Doppler are readily obtained in close to 80%

cm/s 100 E A E A

MITRAL
cm/s 100 S D S D S

PULM VEIN
A

NORMAL

NORMAL LAP

HIGH LAP

( LV STIFFNESS)

LV RELAXATION
Fig 5. Diagrammatic illustration of pulmonary vein velocity and its time relation with transmitral velocity in 3 common hemodynamic conditions: normal relaxation, impaired relaxation, and impaired relaxation with high LA pressure.

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A PV - A MV = 50 ms

Fig 6. Panel A illustrates the transmitral and PVV recorded in a patient with elevated LVEDP. Notice the prolonged duration of the pulmonary vein retrograde A wave relative to the mitral A wave. A PV A MV was 50 milliseconds. Panel B illustrates a simultaneous recording of mitral and LV outflow velocities using PW Doppler. This allows measurement of IVRT, which in this patient is shortened to 67 milliseconds. The transmitral velocity is typical of a pseudonormal pattern.

of patients during a routine examination. Figs 1 and 5 illustrate the typical patterns seen in normal hearts and with diastolic dysfunction. During ventricular systole, atrial relaxation combined with a normal descent of the annulus contributes to a rapid decline in LAP (the x descent) that drives flow into the atrium. This is depicted in the PVV recording as an antegrade flow velocity (S wave). After mitral valve opening, there is a second antegrade velocity (D wave) coincident with the transmitral E velocity; during atrial contraction, there is a small retrograde velocity ( A PV ) into the pulmonary vein. When the x descent is replaced by an elevated v wave (as seen frequently during decompensated systolic heart failure), the S wave becomes diminished and the D wave becomes accentuated in concert with the increase in E velocity described above. An S/D ratio of less than 1 (S/D derived using the integral of the velocities) is an index of elevated mean PCWP that like E/A ratio and DT performs more accurately in patients with depressed LVEF.28,29

During atrial contraction with an elevated LVEDP, LV pressure may rise over LAP producing a reverse gradient that shortens the duration of the transmitral A wave relative to A PV (Fig 6). The interval A PV A MV has been found to relate directly with LVEDP30; whenever A PV A MV exceeds 20 milliseconds, LVEDP is likely to be higher than 20 mm Hg. This finding is fairly reliable as long as the PR interval is within a normal range (ie, neither too short nor too long).

Limitations of Transmitral and Pulmonary Vein Velocities

The early transmitral pressure gradient and, consequently, the E velocity are dependent on 2 factors: active relaxation that acts as a negative (pulling) force and LAP that acts as a positive bpushingQ force. Thus, the normal young subject with superb relaxation and the patient with systolic heart failure and high LAP are both likely to have a similar E velocity and E/A ratio (both are

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also likely to have a third heart sound). Patients with heart failure have impaired relaxation and variable chamber stiffness. The effect of the impaired relaxation is to reduce the E velocity, whereas that of the elevated LAP is to do the opposite; thus, the absolute E velocity recorded is the net summation of these 2 opposing forces. In patients with depressed LVEF, the high atrial pressure and prominent v wave predominate, and, thus, the transmitral velocity demonstrates a pseudonormal or restrictive pattern. By contrast, in patients with diastolic heart failure and normal LVEF, the influence of abnormal relaxation and chamber stiffness is more balanced. These patients often have elevated minimal LV diastolic pressure and increased filling pressures without prominence of the v wave that result in a pattern of type I diastolic dysfunction in the transmitral and PVV.13,29 The only parameter that maintains some sensitivity, although less, is A PV A MV duration.29 However, although infrequent, a pseudonormal or restrictive transmitral velocity pattern may be sometimes seen in patients with

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diastolic heart failure and be mistakenly interpreted as normal diastolic function. Application of the Valsalva maneuver can help by showing regression to type I diastolic dysfunction.22 These patients usually have other clues of diastolic heart failure such as concentric LV remodeling and/or LA enlargement. Because of the complex interaction of LV relaxation and LAP, the transmitral and pulmonary vein velocities cannot detect elevated filling pressures in normal hearts subjected to a high volume load such as in acute mitral regurgitation. These velocities are also very limited in the absence of sinus rhythm and cannot be used to assess diastolic function in the presence of mitral inflow obstruction.

Use of Newer Indices of LV Relaxation

As E velocity reflects the interaction between active relaxation and LAP, correcting E for the influence of relaxation should provide an index of LAP. There are currently 2 new echo-

A Flow Propagation Velocity

C B
Vp

Fig 7. Panels A and B illustrate the methodology to derive the V p with color Doppler and color M-mode. See text for details. Panel C is an illustration of the color M-mode patterns seen in 3 common hemodynamic conditions: normal relaxation, impaired relaxation (IR) with normal (NL) LA pressure (P), and impaired relaxation with high LA pressure.

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impaired relaxation and can be used to distinguish a pseudonormal mitral inflow pattern from a normal.33 In patients with pseudonormal or restrictive patterns, the flow propagation often has a curvilinear appearance (Fig 7) given that the flow comes out of the valve orifice at a high velocity and decelerates as it propagates toward the apex. The ratio of transmitral E to V p is used to correct the E velocity for the influence of relaxation. E/V p has been found to relate well with mean PCWP; a V p/E of more than 2.5 is associated with a mean PCWP of greater than 15 mm Hg.33 E/V p has the added advantage that it can be applied to patients in atrial fibrillation.34

cardiographic techniques that allow the assessment of myocardial relaxation and make such correction possible. Propagation Velocity by Color M-Mode As the ventricle relaxes during early filling, a sequence of intracavitary pressure gradients occur from base to apex that promote the propagation of mitral inflow into the LV cavity. The velocity of this flow propagation can be assessed with color M-mode by placing the Mmode cursor within the mitral inflow and obtaining a recording that contains an edge of uniform color during early filling (Fig 7). The slope of this edge represents the propagation velocity (V p). Shifting the color Doppler zero baseline downward or upward can help in obtaining a distinct color border past the valve leaflets. V p has been shown to be fairly insensitive to changes in LAP31 and to relate inversely with Tau .32 A reduced V p (b40 cm/s) implies

Limitations of the Propagation Velocity

Velocity of propagation and E/V p work particularly well in dilated ventricles. However, it is limited in patients with concentric hypertrophy and small hyperdynamic ventricles. Because of small end-systolic and end-diastolic volumes,

80

LA

Vp = 60 cm/s

5 Ea

E/Vp = 1.3

E/Ea = 16

Fig 8. Example of a patient with systemic hypertension, diastolic heart failure, and a small end-systolic LV volume (panel A; EF N65%). Note in panel B a normal V p of 60 cm/s. The mitral E velocity (panel C) is 80 cm/s resulting in an E/V p of 1.3, consistent with normal mean PCWP. In contrast, Ea from the lateral wall (panel D) in this patient is very reduced (5 cm/s) consistent with impaired relaxation; thus, the E/Ea ratio is 16 indicative of an elevated mean PCWP. See text for details.

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there is little room for propagation to occur and V p may be normal in the presence of impaired relaxation; therefore, E/V p may also be normal despite elevated filling pressures (Fig 8). Other limitations of V p include difficulty with reproducibility due to variability induced by the position of the M-mode cursor, the selection of color baseline shift, and the actual measurement of the slope. Quantitative computerized techniques have been applied with excellent results, but they are not commercially available.32,35 V p cannot be applied in the presence of mechanical inflow obstruction. Myocardial (or Annular) Velocities by Tissue Doppler The complex alignment of myocardial fibers along the left ventricle produces 2 major vectors of contraction, a circumferential and a longitudinal. The longitudinal vector contributes to the descent of the mitral annulus during systole and can be assessed with 2D echo, M-mode recording of annular motion, and, more recently, with tissue

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Doppler. Tissue Doppler uses the same PW Doppler technology used for recording flow velocity modified so that it filters the low amplitude reflections from blood cells and processes those coming from tissue. A PW Doppler sample volume can be placed within a myocardial segment to obtain a recording of myocardial velocity. When this is done from an apical window and the sample volume placed at the base, near the mitral annulus, the recorded velocities reflect the longitudinal vector of contraction and relaxation of that particular wall at the base of the LV (Fig 9). It is very easy to obtain recordings from the septal, lateral, anterior, and inferior corners of the annulus. However, for routine clinical practice, the septal and lateral corners suffice.36 As seen in Fig 9, the velocities recorded consist of a positive systolic wave as the annulus moves toward the apex, an early negative diastolic wave (referred to in the literature as Ea, Em or EV) and a late negative diastolic wave during atrial contraction. Ea has been shown in experimental animal work and in humans to relate well with

Basal Septal Annulus

Basal Lateral Annulus

Sa Sa Aa Ea Aa Ea

Fig 9. Recordings of annular velocity from the septum and lateral corner using tissue Doppler. Sa represents the peak systolic velocity, Ea is the early diastolic velocity, and Aa the atrial velocity.

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Limitations of Ea
Ea has several limitations. Although the measurement is easy to obtain with good reproducibility, it is important that the tissue Doppler program provides a clean signal without blurring to prevent a lower value such as 8 cm/s from being measured as normal (N10 cm/s). This was a problem with some of the older ultrasound instruments but has improved greatly with newer models. Ea is a regional index, and, thus, errors can occur when we extrapolate the result to the entire ventricle, particularly in patients with regional wall motion abnormalities or when there is excessive cardiac translation (given that the velocities are measured relative to the transducer position). For instance, a patient with acute myocardial infarction can have a depressed Ea in the affected wall and an augmented one in a distant site that is compensating with hyperdynamic motion.36 Because of the preload dependency of Ea in normal hearts, the ratio E/Ea does not reflect filling pressures accurately in normal young subjects or in patients with primary mitral regurgitation or pericardial constriction47,48; E/Ea does remain accurate in dilated, depressed ventricles with functional mitral regurgitation.47 Preliminary observations in our laboratory using animal experiments suggest that even in de-

invasive indices of relaxation such as Tau , () dP /dt , and lowest diastolic LV pressure.37,38 In addition, Ea declines gradually with aging concordant with other indices of relaxation39 and is inversely affected by increasing afterload.37,40 In the normally contracting and relaxing heart, Ea is directly altered by changes in preload.37 However, this relation disappears in abnormal hearts with impaired relaxation.41 A reduced Ea (b10 cm/s) implies impaired relaxation and can be used to distinguish a pseudonormal mitral inflow pattern from a normal. Furthermore, as with E/V p, the ratio of E velocity to Ea can be used as an index of LAP. Several reports have observed good correlations between E/Ea and mean PCWP.36,41-45 A ratio of less than 8 is over 90% predictive of a mean PCWP of less than 15 mm Hg, whereas a ratio of 15 or more is over 90% predictive of a mean PCWP of greater than or equal to 15 mm Hg; a nonpredictable range exists when E/Ea is between 9 and 12 (Fig 10A). In this range, the use of other echocardiographic findings such as LA enlargement, pseudonormal transmitral velocity, prolonged A PV A MV, or increased velocity of tricuspid regurgitation may be needed to predict filling pressures better. Importantly, E/Ea can predict filling pressures fairly well in patients with normal EF (Fig 8) including those with hypertrophic cardiomyopathy (Fig 10B),40 as well as in patients with sinus tachycardia and atrial fibrillation.36,42-46

A
LV Filling Pressure (mmHg)

E/Ea

E/Ea

Fig 10. Panel A, Correlation of mean PCWP with E/Ea in a heterogeneous population of patients with a wide range of EF. Panel B, Correlation of LV pre-A pressure with E/Ea in a group of patients with hypertrophic cardiomyopathy. (Adapted from Refs. 41 and 43).

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pressed ventricles Ea still has some preload dependency, particularly at the extremes of high LAPs.49 The clinical correlate of this is seen occasionally in young patients with dilated cardiomyopathy and severe heart failure who, despite having a restrictive mitral inflow pattern, continue to have a normal Ea at the lateral base; Ea in the septum, however, is usually reduced (Fig 11). There is still controversy in the literature as to which site is more reliable, the lateral or the septal base for measuring Ea. In a recent study from our laboratory, E/Ea using the average of the 2 sites provided a good estimate of mean PCWP in dilated ventricles with depressed EF, thus, avoiding the problem illustrated in Fig 11; the same was true for patients with regional wall motion abnormalities.36 However, in patients with normal EF, the lateral wall was found to provide a better estimate of mean PCWP. Timing of Velocities With a decline in myocardial relaxation, Ea not only falls but its onset gets delayed relative to the

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onset of the transmitral velocity (Fig 12).50,51 The time interval between onset of mitral inflow and onset of Ea (T Ea-E) has been shown in experimental animal studies to relate very well with Tau and not to relate with changes in LAP (Fig 13).51 Mean LAP can be estimated by the equation, LAP = LVes eIVRT/Tau , where LVes = end-systolic LV pressure.52 Substituting T Ea-E for Tau and 0.9 systolic blood pressure for LVes allows the noninvasive application of this equation for the estimation of mean PCWP. When tested, the results were accurate across a wide range of LVEF.51 A simplified approach is to use the ratio of IVRT to T Ea-E (Fig 13).51 The use of T Ea-E to assess diastole is still considered a new approach that requires further validation. It might have the advantage of not being affected by inflow obstruction. The main limitation of this method is the lack of a direct measurement of T Ea-E. The interval is derived by measuring the time from the Q wave on the ECG to onset of Ea, and from Q to onset of mitral inflow, and subtracting one from the other (Fig 12).

100cm/s

Septal

Lateral

7cm/s 12cm/s

Fig 11. Example of a patient (aged 25 years) with dilated cardiomyopathy, LVEF of less than 30%, and severe heart failure. Note the restrictive pattern of the transmitral velocity consistent with a mean PCWP of greater than 25 mm Hg. The septal Ea is reduced at 7 cm/s resulting in an increased E/Ea of 14. However, the lateral Ea is 12 cm/s resulting in an E/Ea of 8. This patient also had a very slow propagation velocity. See text for details.

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Mitral Leaflets
400ms

Lateral Annular Velocity

440ms

8cm/s

TEa-E = 40ms
42ms

IVRT/TEa-E = 1.05

IVRT
Fig 12. Transmitral velocity, lateral annular velocity, and IVRT in a 75-year-old hypertensive woman with concentric LVH, normal EF, and diastolic heart failure. The transmitral velocity is elevated (180 cm/s) in part due to annular calcification. Note the delay in onset of Ea relative to the onset of the transmitral velocity; T Ea-E was 40 milliseconds and IVRT/T Ea-E was 1.05. See text for details.

A
80 70 60

B
40

Mean PCWP (mmHg)

R = 0.93 N = 20 P > .001

30

Sens = 91% Spec = 89%

Tau (ms)

50 40 30 20 10 0 10 20 30 40 50

20

10

0 0 5 10 15 20

TEA-E(ms)

IVRT/TEa-E

Fig 13. Correlation between Tau and T Ea-E (panel A), and between mean PCWP and IVRT/T Ea-E (panel B). Sens indicates sensitivity; Spec, specificity. Adapted from Rivas-Gotz C, Khoury DS, Manolios M, et al.51

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Myocardial Strain Rate Strain is tissue deformation in response to an applied force. It represents a fractional change in length (ie, DL /L i). Strain rate is the fractional rate of deformation (ie, [ DL / L i ]/ t ). When 2 objects are moving away from each other, the normalized rate of change in distance between them can be derived as: (V 1V 2)/D 1, where D 1 is the starting distance, and V 1 and V 2 the velocity of the 2 objects. Improvements in color-tissue Doppler technology allow simultaneous assessment of myocardial velocities in multiple regions along the LV wall. With the help of dedicated software, simultaneous measurements of myocardial velocities are obtained at multiple equidistant points and strain rate derived along the LV wall from base to apex. As muscle is incompressible, the longitudinal strain of a segment is inversely related to the change in thickness of that segment. Measurements of systolic and diastolic strain rates provide a new approach to the quantitation of regional function. Because strain is derived from the difference in velocity from 2 adjacent points, the values obtained are less sensitive to cardiac translation. Preliminary studies suggest that strain rate may be superior to myocardial velocities, particularly for the detection of ischemia-induced contraction and relaxation abnormalities.53,54 Strain rate still remains a research tool, in part because it is provided only by one commercial ultrasound system and requires off-line analysis.

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Summary and Recommendations

The availability of new indices of LV relaxation (V p and Ea) enhances the research application of noninvasive techniques in the evaluation of diastolic function. Because they are less influenced by preload, these indices can be used to detect early abnormalities of myocardial function or to study noninvasively the effects of new therapies on LV relaxation. For instance, in familial hypertrophic cardiomyopathy, young subjects affected by the mutation but without detectable hypertrophy by echocardiography have been found to have depressed myocardial velocities by tissue Doppler.55,56 These new indices can also be useful in deriving estimates

of LV chamber stiffness by combining either E/V p or E/Ea with echocardiographic measurements of end-diastolic volume.57 In clinical practice, we recommend that an assessment of LV relaxation be made separate from an estimate of filling pressures. In patients with depressed LVEF, type I diastolic dysfunction can be used as a marker of impaired LV relaxation and normal filling pressures. In most other situations, it is better to use either V p or Ea for the assessment of relaxation, with Ea preferred in hypertrophic hearts with small LV cavities. The transmitral or pulmonary vein velocities are not recommended as they cannot distinguish well the influence of relaxation from that of LAP. For instance, one might interpret a low E/A ratio as a sign of impaired relaxation when the real problem could be a very low LAP secondary to hypovolemia. On the other hand, there are more choices available for the estimation of filling pressures depending primarily on LV size and EF. In patients with dilated ventricles and depressed EF, the mitral E/A ratio, IVRT, deceleration time, and measurements from PVV are excellent indicators of filling pressures and are relatively simple to use. The use of E/V p or E/Ea is not discouraged but may not be required. On the other hand, in patients with normal EF, the transmitral or pulmonary vein velocities are insensitive although specific (as long as V p or Ea confirms the presence of impaired relaxation). The one exception is A PV A MV which may still be valid if one is interested in estimating LVEDP. We therefore recommend using E/V p and/or E/Ea in patients with normal EF, with the latter preferred in hypertrophic hearts with small LV cavities. The application of strain rate awaits further refinements and wider availability.

References
1. Weiss JL, Frederiksen JW, Weisfeldt ML: Hemodynamic determinants of the time-course of fall in canine left ventricular pressure. J Clin Invest 58: 751 - 760, 1976 2. Udelson JE, Bacharach SL, Cannon III RO, et al: Minimum left ventricular pressure during beta-adrenergic stimulation in human subjects: Evidence for elastic recoil and diastolic bsuctionQ in the normal heart. Circulation 82:1174 - 1182, 1990 3. Rahimtoola SH, Loeb HS, Ehsani A, et al: Relationship of pulmonary artery to left ventricular diastolic

ASSESSMENT OF DIASTOLIC FUNCTION pressures in acute myocardial infarction. Circulation 46:283 - 290, 1972 Bonow RO: Radionuclide angiographic evaluation of left ventricular diastolic function. Circulation 84: I208 - I215, 1991 (Suppl 3) Poliner LR, Farber SH, Glaeser DH, et al: Alteration of diastolic filling rate during exercise radionuclide angiography: A highly sensitive technique for detection of coronary artery disease. Circulation 70: 942 - 950, 1984 Seals AA, Verani MS, Tadros S, et al: Comparison of left ventricular diastolic function as determined by nuclear cardiac probe, radionuclide angiography, and contrast cineangiography. J Nucl Med 27:1908 - 1915, 1986 Ishida Y, Meisner JS, Tsujioka K, et al: Left ventricular filling dynamics: Influence of left ventricular relaxation and left atrial pressure. Circulation 74: 187 - 196, 1986 Schiller NB, Shah PM, Crawford M, et al: Recommendations for quantitation of the left ventricle by twodimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 2:358 - 367, 1989 Kircher B, Abbott JA, Pau S, et al: Left atrial volume determination by biplane two-dimensional echocardiography: validation by cine-computed tomography. Am Heart J 121:864 - 871, 1991 Nishimura RA, Tajik AJ: Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinicians Rosetta Stone. J Am Coll Cardiol 30:8 - 18, 1997 Habib GB, Zoghbi WA: Doppler assessment of right ventricular filling dynamics in systemic hypertension: Comparison with left ventricular filling. Am Heart J 124: 1313 - 1320, 1992 Wachtell K, Bella JN, Rokkedal J, et al: Change in diastolic left ventricular filling after one year of antihypertensive treatment: The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study. Circulation 105:1071 - 1076, 2002 Nishimura R, Appleton C, Redfield M, et al: Noninvasive Doppler echocardiographic evaluation of left ventricular filling pressures in patients with cardiomyopathies: A simultaneous Doppler echocardiographic and cardiac catheterization study. J Am Coll Cardiol 28:1226 - 1233, 1996 Quin ones MA: Doppler assessment of left ventricular diastolic function, (ed 2). in Navin C (ed.) Doppler Echocardiography Malvern, PA, Lea & Febiger, 1992, pp 197-215 Sartori MP, Quin ones MA, Kuo LC: Relation of Doppler-derived left ventricular filling parameters to age and radius/thickness ratio in normal and pathologic states. Am J Cardiol 59:1179 - 1182, 1987 Nagueh SF, Kopelen HA, Zoghbi WA: Feasibility and accuracy of Doppler echocardiographic estimation of pulmonary artery occlusive pressure in the intensive care unit. Am J Cardiol 75:1256 - 1262, 1995

353
17. Aurigemma GP, Gottdiener JS, Shemanski L, et al: Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: The Cardiovascular Health Study. J Am Coll Cardiol 37: 1042 - 1048, 2001 18. Tsang TS, Barnes ME, Gersh BJ, et al: Risks for atrial fibrillation and congestive heart failure in patients z65 years of age with abnormal left ventricular diastolic relaxation. Am J Cardiol 93:54 - 58, 2004 19. Choong CY, Abascal VA, Thomas JD, et al: Combined influence of ventricular loading and relaxation on the transmitral flow velocity profile in dogs measured by Doppler echocardiography. Circulation 78:672 - 683, 1988 20. Little WC, Ohno M, Kitzman DW, et al: Determination of left ventricular chamber stiffness from the time for deceleration of early left ventricular filling. Circulation 92:1933 - 1939, 1995 21. Yong Y, Nagueh SF, Shimoni S, et al: Deceleration time in ischemic cardiomyopathy: Relation to echocardiographic and scintigraphic indices of myocardial viability and functional recovery after revascularization. Circulation 103:1232 - 1237, 2001 22. Hurrell DG, Nishimura RA, Ilstrup DM, et al: Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: A simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 30:459 - 467, 1997 23. Temporelli PL, Corra U, Imparato A, et al: Reversible restrictive left ventricular diastolic filling with optimized oral therapy predicts a more favorable prognosis in patients with chronic heart failure. J Am Coll Cardiol 31:1591 - 1597, 1998 24. Hansen A, Haass M, Zugck C, et al: Prognostic value of Doppler echocardiographic mitral inflow patterns: Implications for risk stratification in patients with chronic congestive heart failure. J Am Coll Cardiol 37:1049 - 1055, 2001 25. Vanoverschelde JL, Robert AR, Gerbaux A, et al: Noninvasive estimation of pulmonary arterial wedge pressure with Doppler transmitral flow velocity pattern in patients with known heart disease. Am J Cardiol 75:383 - 389, 1995 26. Pozzoli M, Capomolla S, Pinna G, et al: Doppler echocardiography reliably predicts pulmonary artery wedge pressure in patients with chronic heart failure with and without mitral regurgitation. J Am Coll Cardiol 27:883 - 893, 1996 27. Appleton CP, Galloway JM, Gonzalez MS, et al: Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 22:1972 - 1982, 1993 28. Kuecherer HF, Muhiudeen IA, Kusumoto FM, et al: Estimation of mean left atrial pressure from transesophageal pulsed Doppler echocardiography of pulmonary venous flow. Circulation 82:1127 - 1139, 1990

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

354
29. Yamamoto K, Nishimura RA, Chaliki HP, et al: Determination of left ventricular filling pressure by Doppler echocardiography in patients with coronary artery disease: Critical role of left ventricular systolic function. J Am Coll Cardiol 30:1819 - 1826, 1997 30. Rossvoll O, Hatle LK: Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: Relation to left ventricular diastolic pressures. J Am Coll Cardiol 21:1687 - 1696, 1993 31. Takatsuji H, Mikami T, Urasawa K, et al: A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular filling flow propagation by color M-mode Doppler echocardiography. J Am Coll Cardiol 27:365 - 371, 1996 32. Brun P, Tribouilly C, Duval AM, et al: Left ventricular flow propagation during early filling is related to wall relaxation: A colour M-mode Doppler analysis. J Am Coll Cardiol 20:420 - 432, 1992 33. Garcia MJ, Ares MA, Asher C, et al: An index of early left ventricular filling that combined with pulsed Doppler peak E velocity may estimate capillary wedge pressure. J Am Coll Cardiol 29:448 - 454, 1997 34. Nagueh SF, Kopelen HA, Quin ones MA: Doppler estimation of left ventricular filling pressure in atrial fibrillation. Circulation 94:2138 - 2145, 1996 35. Stqgaard M, Smiseth OA, Risoe C, et al: Intraventricular early diastolic filling during acute myocardial ischemia, assessment by multigated color M-mode Doppler echocardiography. Circulation 88: 2705 - 2713, 1993 36. Rivas-Gotz C, Manolios M, Thohan V, et al: Impact of left ventricular ejection fraction on estimation of left ventricular filling pressures using tissue Doppler and flow propagation velocity. Am J Cardiol 91:780 - 784, 2003 37. Nagueh SF, Sun H, Kopelen HA, et al: Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler. J Am Coll Cardiol 37:278 - 285, 2001 38. Oki T, Tabata T, Yamada H, et al: Clinical application of pulsed Doppler tissue imaging for assessing abnormal left ventricular relaxation. Am J Cardiol 79:921 - 928, 1997 39. Rodriguez L, Garcia M, Ares M, et al: Assessment of mitral annular dynamics during diastole by Doppler tissue imaging: Comparison with mitral Doppler inflow in subjects without heart disease and in patients with left ventricular hypertrophy. Am Heart J 131:982 - 987, 1996 40. Sohn DW, Chai IH, Lee DJ, et al: Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol 30:474 - 480, 1997 41. Nagueh SF, Middleton KJ, Kopelen HA, et al: Doppler tissue imaging: A noninvasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 30:1527 - 1533, 1997 42. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and

ONES QUIN tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 102:1788 - 1794, 2000 Nagueh SF, Lakkis NM, Middleton KJ, et al: Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation 99: 254 - 261, 1999 Sundereswaran L, Nagueh SF, Vardan S, et al: Estimation of left and right ventricular filling pressures after heart transplantation by tissue Doppler imaging. Am J Cardiol 82:352 - 357, 1998 Nagueh SF, Mikati I, Middleton KJ, et al: Doppler estimation of left ventricular filling pressure in sinus tachycardia: A new application of tissue Doppler imaging. Circulation 98:1644 - 1650, 1998 Sohn DW, Song JM, Zo JH, et al: Mitral annulus velocity in the evaluation of left ventricular diastolic function in atrial fibrillation. J Am Soc Echocardiogr 12:927 - 931, 1999 Bruch C, Stypmann J, Gradaus R, et al: Usefulness of tissue Doppler imaging for estimation of filling pressures in patients with primary or secondary pure mitral regurgitation. Am J Cardiol 93:324 - 328, 2004 Ha JW, Oh JK, Ling LH, et al: Annulus paradoxus: Transmitral flow velocity to mitral annular velocity ratio is inversely proportional to pulmonary capillary wedge pressure in patients with constrictive pericarditis. Circulation 28:976 - 978, 2001 Nagueh SF, Rao L, Soto J, et al: Hemodynamic mechanisms that account for the variable effect of preload on tissue Doppler early diastolic velocity. Circulation 107:2306, 2002 (abstract, Suppl 3) Hasegawa H, Little WC, Ohno M, et al: Diastolic mitral annular velocity during the development of heart failure. J Am Coll Cardiol 41:1590 - 1597, 2003 Rivas-Gotz C, Khoury DS, Manolios M, et al: Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: A novel index of left ventricular relaxation: Experimental studies and clinical application. J Am Coll Cardiol 42:1463 - 1470, 2003 Thomas JD, Flachskampf FA, Chen C, et al: Isovolumic relaxation time varies predictably with its time constant and aortic and left atrial pressure: Implications for the noninvasive evaluation of ventricular relaxation. Am Heart J 124:1305 - 1313, 1992 Stoylen A, Slordahl S, Skjelvan GK, et al: Strain rate imaging in normal and reduced diastolic function: Comparison with pulsed Doppler tissue imaging of the mitral annulus. J Am Soc Echocardiogr 14:264 - 274, 2001 Kukulski T, Jamal F, DHooge J, et al: Acute changes in systolic and diastolic events during clinical coronary angioplasty: A comparison of regional velocity, strain rate, and strain measurement. J Am Soc Echocardiogr 15:1 - 12, 2002 Nagueh SF, Bachinski LL, Meyer D, et al: Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

ASSESSMENT OF DIASTOLIC FUNCTION diagnosis before and independently of hypertrophy. Circulation 104:128 - 130, 2001 56. Nagueh SF, McFalls J, Meyer D, et al: Tissue Doppler imaging predicts the development of hypertrophic cardiomyopathy in subjects with subclinical disease. Circulation 108:395 - 398, 2003

355
57. Nagueh SF, Stetson SJ, Lakkis NM, et al: Decreased expression of tumor necrosis factor-alpha and regression of hypertrophy after nonsurgical septal reduction therapy for patients with hypertrophic obstructive cardiomyopathy. Circulation 103: 1844 - 1850, 2001