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- ↵*Reprint requests and correspondence: Dr. Anthony N. DeMaria, Cardiology Division, University of California at San Diego, 200 West Arbor Drive, San Diego, California 92103-8411
Relation of transmitral flow velocity patterns to left ventricular diastolic function: new insights from a combined hemodynamic and Doppler echocardiographic study
by C. P. Appleton, L. K. Hatle, R. I. Popp (2)
In this edition of the Journal, we release the thirteenth in a series of reviews of influential articles that have been previously published in ACC journals, including the American Journal of Cardiology(from 1958 to 1982) and JACC(from 1983 to the present). The publication of these articles is only one aspect of the ACC’s 50th anniversary commemoration, which highlights 50 years of leadership in cardiovascular care and education. The articles are intended to encourage reflection on the remarkable progress made in cardiovascular medicine over time, as well as to acknowledge the amazing prescience of some early investigators in anticipating and, in many cases, later guiding developments in their field.
The working group responsible for selecting these articles and asking reviewers to write editorials solicited suggestions from the ACC’s clinical committees and individual members.
The group achieved consensus fairly easily, including whom the group should ask to prepare the accompanying editorials. We initially drew up a list of 14 general areas to cover in this series, but later found that there are several major areas of modern cardiology, prominently molecular cardiology, in which the truly landmark articles have, alas, not yet been published in JACC. Therefore, the working group decided not to categorize by subject, but instead, to concentrate on the most important articles.
The working group, a task force of the Subcommittee for the Commemoration of the ACC 50th Anniversary, owes a great deal to Ms. May A. Roustom and the efficient and tireless staff at Heart House for facilitating this project. We also wish to thank all who suggested articles and, most important, the authors who prepared reviews for their willingness to contribute their time and wisdom.
Influential Articles in JACC Working Group
Sharon A. Hunt, M.D., F.A.C.C.
Rick A. Nishimura, M.D., F.A.C.C.
H.J.C. Swan, M.D., Ph.D., M.A.C.C.
Michael J. Wolk, M.D., F.A.C.C.
In an effort to determine what clinically useful information regarding left ventricular diastolic function can be inferred noninvasively with pulsed wave Doppler echocardiography, mitral flow velocity patterns and measured variables were correlated with hemodynamic findings in 70 patients: 30 with coronary artery disease, 20 with idiopathic congestive cardiomyopathy, 14 with a restrictive myocardial process and 6 without significant cardiac disease. The effect of sudden changes in hemodynamics on the mitral flow velocity pattern was also investigated in a subgroup of patients who had simultaneous recording of mitral flow velocity and left ventricular pressure before and after left ventriculography. Mitral flow velocity recordings from 30 healthy adults served as a reference group. This analysis suggests that 1) the majority of patients with these cardiac disorders demonstrate abnormal mitral flow velocity patterns or variables; 2) markedly different flow velocity patterns can be seen in patients with impaired left ventricular relaxation; 3) the different mitral patterns appear to relate more to myocardial function and hemodynamic status than to the type of disease process present; 4) certain mitral patterns suggest different filling pressures and rates of early diastolic left ventricular filling; 5) an increase in left atrial pressure can “normalize” an abnormal mitral flow velocity pattern and “mask” a left ventricular relaxation abnormality; and 6) the different patterns appear to represent a dynamic continuum with the potential to change from one to another as a result of disease progression, medical therapy or sudden changes in hemodynamics. It is co.ncluded that, despite the indirect method of estimation and certain limitations, mitral flow velocity recordings have clinical potential in assessing left ventricular diastolic function that merits further investigation. Originally published in the Journal of the American College of Cardiology, August, 1988.
The role of diastolic function in human health and disease remains enigmatic, primarily because of the difficulty in assessment by physical examination or even by direct invasive measurements. The advent of echocardiography provided the ability to assess global left ventricular (LV) filling dynamics by transmitral Doppler velocity recordings and offered the potential to diagnose diastolic abnormalities (1). In 1988, Appleton et al. (2)reported the initial in-depth correlation between transmitral dynamics and invasively determined measurements of pressure and flow. In so doing, these investigators provided the basis for the identification and pathophysiologic classification of diastolic dysfunction by echocardiography. Although noninvasive assessment is imperfect and continues to evolve, Appleton’s report established the feasibility of using Doppler echocardiography to assess diastolic behavior, and opened a field of interest that has been termed “diastology.”
Diastolic function is complex and has several determinants, including the active energy-consuming process of relaxation, chamber and tissue stiffness (or its opposite, compliance), atrial contraction and the modifying factors of ventricular interaction and pericardial restraint. Therefore, no single criterion has been established that completely characterizes diastolic performance and accurately identifies abnormalities (3). Catheter-based invasive techniques have provided the gold standard to date and have been used to assess LV pressures (tau, peak dP/dt) or, more commonly, the relationship between pressure and volume measurements during diastole. If normal diastolic function is defined as the ability to accept adequate filling volume at low pressure, the most accurate indexes would require pressure recording. Because such measurements necessitate catheterization, noninvasive techniques have focused on the delineation of volume changes as markers of diastolic performance, although it has been recognized that this approach is imperfect.
The initial noninvasive evaluation of diastolic filling dynamics included M-mode LV dimensions or radionuclide LV counts (4). The advent of pulsed Doppler spectral recordings enabled investigators to define patterns of global LV filling velocities. If one assumes a relatively constant area for the mitral annulus throughout diastole, velocity recordings from this site represent volumetric changes. However, higher quality signals are generally obtained with a sample volume positioned at the tips of the mitral valve leaflets. In either case, Doppler recordings yielded a bipeaked filling pattern with individual velocity peaks, one occurring during rapid, passive ventricular filling in early diastole (E) and another after atrial contraction in late diastole (A) (1). As was true with other modalities, peak early filling velocities were observed to predominate over those caused by atrial contraction.
The earliest deviation of transmitral Doppler recordings from normal (i.e., reversal of the predominance of the E and A velocities) was thought to represent diminished compliance and generated enthusiasm for the value of echocardiography in assessing diastolic function. However, studies subsequently revealed normal compliance measurements in patients with E to A reversal. More significantly, the magnitudes of E and A velocities were found to have several determinants independent of diastolic properties, including ventricular preload, heart rate, patient age and even location of the Doppler sample volume (5). Accordingly, the pendulum swung, and the unbridled enthusiasm for the echocardiographic assessment of diastolic performance was replaced by the belief that Doppler methodology was of little value.
It was in this context that Appleton et al. (2)published their classic study relating transmitral filling velocities to direct hemodynamic values. In a group of patients with a variety of cardiac disorders, they measured intracardiac pressures and flows, including LV end-diastolic and pulmonary artery wedge pressure, the time constant of LV pressure fall during isovolumic relaxation (tau), peak negative dP/dt and stroke volume. They observed a spectrum of aberrations of Doppler transmitral flow, even in patients who had certain aspects of diastolic dysfunction in common, such as impaired early relaxation. Appleton et al. (2)observed that these transmitral velocity patterns could be related to two hemodynamic profiles independent of the type of disease present. They described a transmitral filling pattern consisting of a decreased peak early (E) velocity and deceleration rate and an increased atrial (A) velocity and isovolumic relaxation time. This occurred with impaired LV relaxation and normal or nearly normal left atrial pressures. A second configuration that was delineated included an increase in peak E velocity and deceleration rate with a concomitant reduction in isovolumic relaxation time and A velocity. This second constellation was observed in patients with increased left atrial pressures and a restrictive type of physiology in which LV pressure manifested a rapid early rise followed by an abrupt plateau in mid to late diastole. These two individual profiles were referred to as “impaired relaxation” and “restrictive filling,” respectively, and they were soon found to have differing clinical significance, with the restrictive type of patient being more symptomatic (6). Not surprisingly, hemodynamic components of each of the individual abnormal filling types often coexisted and resulted in a hybrid pattern of transmitral filling dynamics without evidence of dysfunction, termed “pseudonormal.”
From the careful hemodynamic data collected by Appleton et al. (2), certain concepts evolved regarding the pathophysiologic mechanisms responsible for the abnormal filling dynamics observed by Doppler echocardiography. Left ventricular filling was considered as a composite effect of rapid early diastolic flow generated by the suction-like effect of LV relaxation, and late atrial flow produced by the positive hydrodynamic forces of left atrial contraction. In patients with impaired or prolonged ventricular relaxation, intracardiac pressures would be unaffected, but the delayed and diminished left atrial to LV early diastolic pressure gradient would result in less suction, a decreased early filling velocity and a prolonged deceleration time. By contrast, in patients in whom LV distensibility was reduced because of increased intrinsic stiffness or operating compliance, left atrial pressure would be increased. This elevated left atrial pressure would result in an increased early diastolic flow velocity engendered by greater hydrodynamic forces and in a shorter isovolumic relaxation time. The decrease in mid to late diastolic distensibility would produce a more rapid transmitral pressure equilibration, resulting in decreased deceleration time as well as diminished flow velocities in response to atrial contraction. In the setting of pseudonormalization, increased left atrial pressures would offset the reduced flow related to impaired relaxation and result in relatively normal early and late filling velocities and deceleration time.
The two abnormal transmitral filling patterns described by Appleton et al. (2)were soon found to be of value in identifying diastolic dysfunction and were observed to correlate with functional impairment and adverse prognosis (6,7). However, because the clinical application of transmitral Doppler recordings was confounded by the pattern of pseudonormalization, additional markers were sought. The pattern of Doppler flow signals recorded from the pulmonary veins provided precisely such a marker (8). In normal subjects, pulmonary venous recordings consisted of forward systolic and diastolic flow velocities of approximately equal magnitudes, with a short, low-velocity flow reversal into the veins after atrial contraction. In patients in whom an increased left atrial pressure coexisted with impaired relaxation to yield pseudonormalization, an A flow reversal of increased duration and velocity, often with a diminished systolic component, could frequently be observed in the pulmonary veins.
The use of pulmonary venous flow tracings was subsequently extended to the assessment of LV end-diastolic pressure (8). In the setting of an increased LV end-diastolic pressure, increased LV impedance should favor reversed flow into the pulmonary veins rather than forward transmitral flow after atrial contraction. Although this augmented flow reversal may be manifested by a greater velocity, it is most reliably evidenced by an increased flow duration. Thus, a pulmonary venous A flow reversal greater in duration than the duration of the forward A flow velocity has been shown to indicate an elevated LV end-diastolic pressure, and the magnitude of the difference has been related to the level of pressure elevation.
Spectral Doppler velocity measurement continues to provide the cornerstone on which diastolic function is evaluated by echocardiography because it is readily recorded and easily analyzed. However, several additional echocardiographic approaches have subsequently been devised to assess filling dynamics. In the setting of diastolic dysfunction, the rate of propagation of blood into the LV is diminished, a phenomenon most readily evaluated by color M-mode Doppler echocardiography performed in the apical four-chamber view (9). Such color M-mode Doppler recordings reveal both early diastolic and atrial flow streams, the slopes of which are functions of the transit rate of intracardiac LV filling. Color M-mode Doppler recordings exhibit a striking reduction in the slope of early filling with restrictive diastolic dysfunction and a milder reduction in the presence of impaired relaxation.
Most recently, technology has been developed to obtain spectral Doppler velocity measurements from the myocardium itself, so-called “tissue Doppler recordings.” Myocardial velocities are less influenced by transmitral pressure gradients than are flow velocities (10). Accordingly, peak A velocities are reduced in the presence of impaired relaxation, whether this abnormality occurs alone or in conjunction with pseudonormalization. Thus, color M-mode and tissue Doppler recordings provide additional methods both to identify diastolic dysfunction and to distinguish pseudonormalization.
The constellation of echocardiographic methods described earlier provides a useful approach to the diagnosis of diastolic dysfunction. Normal values have been established for transmitral and pulmonary venous flow velocities, the rate of flow propagation on color M-mode Doppler echocardiography and diastolic tissue velocities (11). In the absence of physiologic variables capable of altering diastolic filling patterns, particularly reduced preload and advanced age (>55 years), reversal of the E to A peak velocity ratio and prolongation of deceleration time indicate impaired LV relaxation. An E flow velocity greater than twice the A flow velocity, or a deceleration time <150 ms, identifies the restrictive pattern of filling. Pulmonary vein, color M-mode echocardiography and spectral Doppler tissue velocities confirm the presence of these abnormalities by exhibiting similar changes in early and late flow and may be of particular value in unmasking pseudonormalization. Therefore, cardiac ultrasound provides a strategy by which to identify and classify diastolic dysfunction and even to quantify the severity of the abnormality.
On the basis of these echocardiographic findings, one can also derive estimates of prognosis, functional disability and level of LV end-diastolic pressure in patients with diastolic dysfunction. Left ventricular filling dynamics manifesting impaired relaxation have been found to evolve into restrictive patterns as the disease progresses. Several studies have now demonstrated that filling dynamics consistent with restrictive physiology convey a significant mortality risk in patients with congestive heart failure of any etiology—greater, in fact, than even ejection fraction (12). Echocardiographic measurements provide a means to follow the progression of disease and may even form the basis for therapeutic decisions. For example, it is likely that preservation of diastolic filling time and atrial contraction by heart rate control would be of much greater importance in patients in whom LV filling occurs predominantly in late diastole with atrial contraction than in those with restrictive physiology.
For years, the clinical diagnosis of diastolic dysfunction has consisted of finding normal systolic performance in patients with signs and symptoms of cardiac disease. In fact, completely accurate techniques to measure diastolic function are still lacking, even using invasive methods. By carefully relating the time course of transmitral filling dynamics that are derived from echocardiography to intracardiac pressures and flow, Appleton et al. (2)laid the foundation for applying noninvasive measurements to the evaluation of diastolic function. With the additional data provided by pulmonary vein, color M-mode and spectral Doppler tissue recordings, echocardiography now provides a clinically useful technique for assessing diastolic abnormalities. The diagnosis of diastolic dysfunction can therefore now be based not only on exclusion of systolic abnormalities, but also on positive evidence of disordered diastolic properties. The pendulum has now swung back to the recognition that, despite its significant limitations, echocardiography can make valuable contributions to the evaluation of diastolic function. It is instructive to note that the assessment of diastolic function by echocardiography provides a quintessential example of the importance of understanding the basic mechanisms underlying the generation of noninvasive data. By defining the pressure and flow determinants of transmitral LV filling dynamics, Appleton et al. (2)paved the way for the clinical application of echocardiography to the assessment of diastolic dysfunction and to the present-day field of diastology.
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