Echocardiographic Evaluation of Diastolic Function Can Be Used to Guide Clinical Care

Abstract

HomeCirculationVol. 120, No. 9Echocardiographic Evaluation of Diastolic Function Can Be Used to Guide Clinical Care Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBEchocardiographic Evaluation of Diastolic Function Can Be Used to Guide Clinical Care William C. Little, MD and Jae K. Oh, MD William C. LittleWilliam C. Little From the Section of Cardiology, Wake Forest University School of Medicine, Winston-Salem, NC (W.C.L.), and Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn and Cardiac and Vascular Center, Samsung Medical Center, Seoul, Korea (J.K.O.). Search for more papers by this author and Jae K. OhJae K. Oh From the Section of Cardiology, Wake Forest University School of Medicine, Winston-Salem, NC (W.C.L.), and Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn and Cardiac and Vascular Center, Samsung Medical Center, Seoul, Korea (J.K.O.). Search for more papers by this author Originally published1 Sep 2009https://doi.org/10.1161/CIRCULATIONAHA.109.869602Circulation. 2009;120:802–809For normal cardiac performance, the left ventricle (LV) must be able to eject an adequate stroke volume at arterial pressure (systolic function) and fill without requiring an elevated left atrial (LA) pressure (diastolic function). These systolic and diastolic functions must be adequate to meet the needs of the body both at rest and during stress.Response by Tschöpe and Paulus on p 809Systolic function is conveniently (although not always accurately) measured as the ejection fraction (EF), calculated as stroke volume divided by end-diastolic volume.1 The LV EF is easily interpreted. The lower limit of normal is ≈50%. The lower the EF is, the greater the reduction in systolic function. Diastolic function has been more difficult to evaluate.2 Traditionally, invasive measures of LV diastolic pressure-volume relations and the rate of LV pressure fall during isovolumetric relaxation have been used. However, these methods are not practical for routine clinical use and do not adequately evaluate all aspects of diastolic filling.3Comprehensive echocardiographic evaluation of the dynamics of LV filling using blood pool and tissue Doppler has now progressed so that it provides clinically important information that can be used to direct patient care. We present data that support the use of echocardiographic evaluation of diastolic function to recognize cardiac dysfunction in patients with heart failure, especially those with preserved EF; to guide the management of patients by identifying those with and without elevated left filling pressures regardless of underlying EF; and to determine prognosis in a wide variety of patient populations.LV FillingAlthough the LV end-diastolic pressure-volume relation describes the passive properties of the LV, LV filling is not a passive or slow process.3 In fact, the peak flow rate across the mitral valve is equal to or greater than the peak flow rate across the aortic valve. Understanding the physiological basis of LV filling provides the basis for the interpretation of the information available from a comprehensive echocardiographic evaluation of LV filling dynamics.During LV ejection, energy is stored as the myocytes are compressed and the elastic elements in the myocardial wall are compressed and twisted.4 Relaxation of myocardial contraction allows this energy to be released as the elastic elements recoil. This causes LV pressure to fall rapidly during isovolumetric relaxation. Furthermore, for the first 30 to 40 milliseconds after mitral valve opening, relaxation of LV wall tension is normally rapid enough to cause the LV pressure to continue to decline despite an increase in LV volume.5 This fall in LV pressure produces an early diastolic pressure gradient from the LA that extends to the LV apex (Figure 1).6 This accelerates blood out of the LA and produces rapid early diastolic flow that quickly propagates to the apex. Because the diastolic intraventricular pressure gradient pulls blood to the apex, it can be considered a measure of LV suction. It is reduced in experimental models of heart failure4,7 and ischemia8 and in patients with ischemia,9 hypertrophic cardiomyopathy,10 and heart failure.11Download figureDownload PowerPointFigure 1. Recording of pressure at the apex of the LV, LA pressure, and LV filling rate in a conscious animal. Data for this previously unpublished figure from Cheng et al.5The rate of early LV filling is determined by the pressure gradient from the LA to the LV apex (Figure 1).5 Although peak filling occurs after the peak pressure gradient, the 2 are closely related. The lower the early diastolic LV pressure is, the greater the gradient for filling, allowing the heart to fill without requiring elevated LA pressure. Furthermore, the ability to decrease LV early diastolic pressure in response to stress allows an increase in LV stroke volume without much increase in LA pressure.7 LV relaxation is very sensitive to myocardial dysfunction, and the ability to increase LV filling without an increase in LA pressure is reduced or absent in heart failure.7,12After filling of the LV begins, the pressure gradient from the LA to the LV apex decreases and then transiently reverses (Figure 1). The reversed mitral valve pressure gradient decelerates and then stops the rapid flow of blood into the LV early in diastole. The time for flow deceleration is determined predominantly by the functional LV chamber stiffness and provides a noninvasive indication of LV diastolic operating stiffness.13–15During the midportion of diastole (diastasis), the pressure in the LA and LV equilibrates and mitral flow nearly ceases. Late in diastole, atrial contraction produces a second LA-to-LV pressure gradient that again propels blood into the LV. After atrial systole, as the LA relaxes, its pressure decreases below LV pressure, causing the mitral valve to begin closing. The onset of ventricular systole produces a rapid increase in LV pressure that seals the mitral valve and ends diastole.The dynamics of LV filling and their alteration with diastolic dysfunction are noninvasively assessed from Doppler measurement of mitral inflow velocity and tissue Doppler assessment of mitral annular velocity. Under normal circumstances, the peak early mitral inflow velocity (E) substantially exceeds the peak velocity during atrial contraction (A). Thus, the E/A ratio is >1.Because the LV apex remains fixed during the cardiac cycle, the mitral annular velocity provides a measure of long-axis lengthening rate. Under normal conditions, peak early diastolic mitral annular velocity (e′, which has also been called Ea, E′, and EM) occurs coincidentally with the mitral E (Figures 2 and 3).16,17 This is a manifestation of the symmetrical expansion of the LV in early diastole as blood moves rapidly to the LV apex in response to a progressive pressure gradient from the left atrium to the LV apex. Under normal circumstances, both E and e′ respond to changes in the LA-to-LV pressure gradient. For example, both E and e′ normally increase in response to volume load and exercise.17–19Download figureDownload PowerPointFigure 2. Recordings in a conscious animal obtained in sinus rhythm during the development of progressive LV dysfunction produced by rapid pacing. See text for discussion. P indicates pressure. Data for this previously unpublished figure from Hasegawa et al.16Download figureDownload PowerPointFigure 3. The stages of diastolic dysfunction recognized by changes in LV filling dynamics.In the presence of mild diastolic dysfunction with slow LV relaxation but without an increase in LA pressure, the early diastolic pressure gradient that accelerates flow is decreased as a result of a higher LV pressure (Figure 2).20 This results in a decrease in both the E and e′ and an increase in the importance of atrial contraction, producing an E/A ratio <1 (Figures 2 and 3). The delayed relaxation results in a prolongation of E-wave deceleration time (DT) and may be associated with a middiastolic peak of mitral flow (L wave).21,22 With increased flow from the LA to LV with atrial contraction, the LA is relatively empty at the beginning of systole, which results in increased systolic velocities in the pulmonary veins toward the LA. This filling pattern has been called an impaired relaxation pattern or grade 1 diastolic dysfunction.1,23 In most patients with impaired relaxation pattern, the mean LA pressure is not elevated despite an increased LV end-diastolic pressure that is maintained by a vigorous atrial contraction.With progressive worsening of diastolic dysfunction associated with an increase in LA pressure, the early diastolic pressure gradient is restored despite increased diastolic LV pressures, resulting in a return of the E wave to the normal range (pseudonormal mitral inflow pattern or grade 2 diastolic dysfunction). Displacement of the LV onto a steeper portion of the pressure-volume curve results in a shortening of the DT.13With slower relaxation, the e′ is delayed, occurring after the E. This indicates that the LV is not expanding symmetrically in diastole but that propagation of filling to the apex and longitudinal expansion occur slowly after the LV is filled by movement of blood from the LA into the LV inflow tract. In the presence of slow relaxation, e′ does not occur during the time of the LA-to-LV pressure gradient, so e′ is reduced and becomes almost independent of LA pressure.16 Both the mitral annular e′ and the delay in e′ relative to E correlate with the time constant of LV isovolumetric pressure decline.16,24 Thus, the pseudonormal mitral inflow pattern is distinguished from normal by a reduced and delayed e′ and increase in the E/e′ ratio (Figures 2 and 3).With even more severe diastolic dysfunction with markedly slowed relaxation and elevated LA pressure, the E increases further, DT becomes very short, and e′ is further reduced and delayed, resulting in a marked elevation of E/e′ (Figures 2 and 3). With severe diastolic dysfunction, the late diastolic annular velocity (a′) also may be reduced, and pulmonary venous systolic forward flow velocity is reduced and less than diastolic forward flow velocity. Other indicators of diastolic dysfunction can be obtained from color M-mode imaging, Doppler echocardiography, and strain-rate imaging.25The presence of pseudonormalized and restricted filling patterns with elevated E/e′ indicates the presence of both diastolic dysfunction (impaired relaxation and elevated LV early diastolic pressures) and elevated LA pressure.17 In contrast, the impaired relaxation pattern indicates diastolic dysfunction without a marked elevation in mean LA pressure.Evaluation of Patients With Heart FailureA comprehensive echocardiographic examination (including imaging and Doppler evaluation) is an important part of the evaluation of all patients with heart failure. Echocardiography provides assessment of the size of the cardiac chambers, LV regional wall motion, and EF, as well as evaluation of valvular function, assessment of the presence of pericardial disease, and an estimation of pulmonary artery pressure.26 This information should be obtained in all patients being evaluated for heart failure. The comprehensive evaluation of diastolic function is also an essential part of an echocardiographic evaluation of the patient with possible heart failure that provides additional clinically important information.The presence of a reduced EF in a patient with the clinical picture consistent with heart failure objectively confirms the presence of a cardiac abnormality, increasing the probability that the patient actually has heart failure. As such, a reduced EF has been used as an entry criterion for most of the large randomized trials that guide our therapy of heart failure.1 However, it is now recognized that many patients have real heart failure without a clear reduction in the LV EF below 50%.27 Such heart failure with preserved EF is most common in elderly patients, particularly women, who may make up the majority of patients with heart failure. It is possible that signs and symptoms of heart failure in a patient with a preserved EF (or even a reduced EF) may not actually be due to heart failure.28 For example, the clinical picture might be due to obesity, lung disease, and/or deconditioning. Thus, it is important to demonstrate objectively that these patients have cardiac dysfunction. Almost all patients with heart failure, regardless of EF, have diastolic dysfunction.29,30 In contrast, a normal e′ (>8 cm/s medial or >10 cm/s lateral) is very unusual in a patient with heart failure (unless the patient has pericardial constriction) and indicates the need to look for other causes of the patient’s symptoms.31Lam et al32 found that e′ was reduced and E/e′ was increased in patients with heart failure and a normal EF compared with both normal subjects and patients with hypertension without heart failure. Similarly, Kasner et al33 observed that an elevated E/e′ ratio was the best noninvasive measure of diastolic dysfunction for distinguishing patients with heart failure and a preserved EF with invasively proven diastolic dysfunction from normal subjects. Consistent with these observations, the European Society of Cardiology consensus statement on how to diagnose diastolic heart failure suggests that an E/e′ ratio >15 alone or an E/e′ >8 in combination with an elevated B-type natriuretic peptide >200 pg/mL can be used as the simplest noninvasive objective indication of diastolic dysfunction to confirm the presence of diastolic heart failure.34Two-dimensional echocardiography also provides clinical clues about diastolic function. The extent of mitral annular motion from the parasternal and apical views provides visual assessment of myocardial relaxation. LA volume is an important structure for the assessment of diastolic function and LV filling pressure. It is unlikely for a patient to have abnormal diastolic dysfunction with normal LA volume. However, not all increased LA volumes indicate diastolic dysfunction and can be seen in patients with mitral regurgitation. In this situation, the e′ velocity is usually normal.The 2-dimensional echocardiography features may be able to identify an underlying cause of diastolic dysfunction. Examples include cardiac amyloid with increased wall thickness and low QRS voltage on ECG, hypertrophic cardiomyopathy with dynamic LV outflow tract obstruction, and thick ventricular septum, noncompaction with increased trabeculation, primary restrictive cardiomyopathy, constrictive pericarditis, or hypertensive heart disease.Determination of LV Filling PressureThe mean LA pressure is the source pressure for LV filling. Determining the LV filling pressure is a key element in the diagnosis and management of patients with suspected decompensated heart failure.35 Measurement of the pulmonary capillary wedge pressure with the Swan-Ganz catheter has become the gold standard for determining LV filling pressure. This invasive procedure can produce complications, especially in critically ill patients. Two randomized clinical studies found no benefit from the use of the Swan-Ganz catheter to manage critically ill patients.36,37 Thus, efforts to find a noninvasive method of determining LV filling pressure have continued.Several diastolic parameters obtained from a comprehensive echocardiographic examination provide information on whether LA pressure is elevated.38 For example, enlargement of the LA correlates with chronic elevations of the LA pressure. A restricted filling pattern with a short DT indicates elevated LA pressure. An abnormal pulmonary venous flow pattern also is seen with an elevated LA pressure. Furthermore, elevated LA pressure usually is associated with some degree of pulmonary hypertension.39 The systolic pulmonary artery pressure can be estimated by calculating the tricuspid valve gradient from the Doppler measurement of the velocity of the tricuspid regurgitation jet. The most common cause of increased pulmonary artery systolic pressure in adults is elevated LA pressure, and the echocardiographic parameters best correlated with pulmonary artery systolic pressure are DT and E/e′.40All of the measures discussed above are useful in identifying patients with or without elevations of LA pressure. However, the most commonly used and easiest-to-interpret parameter to estimate LA pressure is the E/e′ ratio. As discussed, the mitral E wave is augmented when there is an increased LA-to-LV pressure gradient. The e′ is reduced and delayed in the presence of slow relaxation. Thus, a high E and a low e′ (ie, increased E/e′ ratio) indicates that the increased E was due to an elevation of LA pressure, not a fall in LV diastolic pressure. E/e′ has been found to correlate with pulmonary capillary wedge pressures in a wide range of patients studied in multiple laboratories.23 It has a stronger correlation with pulmonary capillary wedge pressure than B-type natriuretic peptide.41 An E/e′ >15 has been found to clearly indicate elevated pulmonary capillary wedge pressure, whereas an E/e′ <8 is associated with normal LA pressure (Figure 4).42 In the intermediate range, an assessment of LA pressure should include the evaluation of other echo Doppler parameters associated with increased LA pressure (ie, LA size, LV filling pattern, DT, isovolumetric relaxation time, and presence of pulmonary hypertension).23Download figureDownload PowerPointFigure 4. LV filling pressure (measured as mean LV diastolic pressure) defined by values of E/e′. ○ Indicates EF <50%; •, EF >50%. Reproduced from Ommen et al42 with permission of the publisher. Copyright © 2000, the American Heart Association.The cutoff value of E/e′ of 15 to recognize elevated LA pressure was obtained using e′ velocity from the medial mitral annulus. Because e′ velocity from the lateral annulus is usually higher than the medial e′ velocity, the cutoff should be adjusted to 12 if the lateral annular velocity is used. An average of the medial and lateral annular velocities has been recommended,23 but as long as there is no basal regional LV wall motion abnormalities, the consistent use of 1 annular velocity should be adequate in clinical practice. We prefer using the medial annular velocity because it is helpful in differentiating myocardial disease from constrictive pericarditis.There are several situations when E/e′ may not provide an accurate assessment of pulmonary capillary wedge pressure. First, in a normal heart, e′ occurs coincidentally with E and responds to changes in LA pressure. For example, E/e′ was not increased but actually decreased in response to massive fluid loading in normal experimental animals.17 However, because LA pressure is rarely elevated in patients with a normal heart,38 the failure of E/e′ to recognize elevated LA pressures in normal subjects is of little clinical importance. Furthermore, E/e′ can distinguish an overfilled normal LV (decreased E/e′) from elevated LA pressure associated with cardiac dysfunction (elevated E/e′).17 Second, E/e′ does not increase in patients with constrictive pericarditis despite elevated pulmonary capillary wedge pressures.43 In fact, the medial e′ increases as constriction becomes worse, which results in a decrease in E/e′ as constriction gets more severe and diastolic filling pressure increases (annulus paradoxus). The lateral annular velocity may be decreased and often is lower than the medial annular velocity in constriction. If a patient has clinical signs of heart failure, especially with increased jugular venous pressure, a normal or increased medial e′ velocity strongly suggests constrictive pericarditis. Third, E/e′ may not provide an estimate of LA pressure in patients with mitral stenosis or mitral regurgitation, especially without a reduction in EF.23,44 Intuitively, the mitral annular velocity should not work as well in patients with aortic or mitral valve replacement and in patients with mitral annulus calcification. However, this issue has not been systematically evaluated. Fourth, although E/e′ correlates with LA pressure in patients with hypertrophic cardiomyopathy, there is substantial scatter limiting its use alone in an individual patient.45Recent ConcernsA recent publication and associated editorial in Circulation raised concerns about the accuracy of the use of E/e′ for patient management.35,46 Mullens and colleagues46 from The Cleveland Clinic assessed the reliability of E/e′ as a predictor of pulmonary capillary wedge pressure in 106 patients with advanced decompensated heart failure. These patients underwent simultaneous Swan-Ganz catheterization and Doppler echocardiography after admission for clinical decompensation. In these patients, E/e′ correlated poorly with pulmonary capillary wedge pressure. Overall, the E/e′ ratio was similar among patients with pulmonary capillary wedge pressure >18 and <18 mm Hg. Finally, there was no direct association of changes in pulmonary capillary pressure and changes in the E/e′ ratio.The failure of E/e′ to perform adequately as a measure of LA pressure in these patients may result at least partially from the characteristics of the patients studied. Significant mitral regurgitation was present in nearly a quarter of the patients. E/e′ may not correlate well with pulmonary capillary wedge pressure in patients with mitral regurgitation.23 Second, half of the patients had undergone cardiac resynchronization therapy, and most had a prolonged QRS with variable degrees of mechanical dyssynchrony. There are also potential questions about the measurement of the filling pressure in these patients. This was accomplished by use of the pulmonary capillary wedge pressure, which may not accurately reflect LA pressure in all situations and is prone to error in patients with pulmonary arterial hypertension.In addition, the technical quality of the mitral inflow and mitral annular velocity recordings in the figures included in the publication is not optimal. It is surprising that so many of the patients had nearly normal pulmonary capillary wedge pressures within 12 hours of admission for decompensated heart failure so severe that it required invasive monitoring. Finally, E/e′ was used in isolation to characterize the LV filling pressure in these patients. In contrast, E/e′ should be used as part of a comprehensive echocardiographic evaluation of patients with heart failure.23,26Echocardiographic Diastolic Assessment to Guide Heart Failure TreatmentComprehensive echocardiographic assessment of diastolic function can help guide the management of patients with heart failure. Optimally, heart failure therapy should maximize diastolic reserve. Correction of the underlying myocardial problem can improve myocardial relaxation, which will be apparent as an increase in e′. However, in most patients with heart failure, e′ remains depressed. In these patients, the most optimal filling pattern achievable is usually an impaired relaxation pattern, with E/A <1 indicating relatively normal LA pressure.47 Once this is achieved, there is little to be gained from further diuresis. It may be helpful to maintain sinus rhythm in this situation so that the important atrial contribution to LV filling is not compromised.In patients with echocardiographic evidence of increased filling pressure, diuresis and preload reduction may improve diastolic reserve and symptoms. If a restrictive LV filling pattern persists after optimal treatment of heart failure, a poor prognosis is indicated.47 Because stroke volume is limited in this situation, bradycardia should be avoided. The LV filling pattern also helps in the programming of the atrial-ventricular interval in patients with pacemakers.48Although medical therapy improves heart failure symptoms, it is often difficult to assess clinically whether an optimal filling pressure is achieved. If a patient continues to have increased filling pressure with a minimal diastolic reserve, development of recurrent heart failure symptoms and hospitalization are frequent.47 Documentation of normal filling pressure or the pattern of impaired relaxation without increased filling pressure is very helpful to know that a patient’s treatment is optimized (Figure 5). Download figureDownload PowerPointFigure 5. Mitral inflow and medial mitral annular velocities before and after treatment in a 73-year-old woman with a normal LV EF admitted with dyspnea. Before therapy, the mitral annular e′ velocity is 5 cm/s, indicating markedly impaired myocardial relaxation. The LV filling pattern is restricted, and the E/e′ ratio is 30. This indicates that the LA pressure is elevated and provides objective evidence that the patient has heart failure. After diuresis and control of hypertension, the filling pattern has changed to impaired relaxation. The mitral annular velocity has not increased, but the E/e′ has fallen to 10. This indicates that the LV filling pressure has been reduced to a normal level.PrognosisEchocardiographic findings of diastolic function provide important prognostic information in a wide variety of patients. A normal filling pattern in community-dwelling subjects indicates an excellent prognosis (Figure 6).49 In contrast, an abnormal filling pattern and progressively greater abnormalities of LV filling pattern (impaired relaxation versus pseudonormalized and restricted filling) indicate subjects with a progressively increased risk of subsequent mortality. The stage of diastolic dysfunction correlates with the impairment of exercise capacity in patients without myocardial ischemia; LV EF does not.50 In patients with heart failure, the stage of diastolic dysfunction is a stronger predictor of mortality than EF.29Download figureDownload PowerPointFigure 6. Kaplan-Meier mortality curves for subjects living in the community. Mortality increases with increasing diastolic dysfunction, apparent as abnormal LV filling patterns. Reproduced with permission from Redfield et al.49 Copyright © 2003. All rights reserved.A short DT indicates an increased LV operating stiffness, is a hallmark of restrictive filling pattern, and denotes poor prognosis in patients after myocardial infarction, dilated cardiomyopathy, and heart transplantation; in those with hypertrophic cardiomyopathy; and in patients with restrictive cardiomyopathy (Figure 7).23 Both pseudonormalized and restricted filling patterns indicate a 4-fold increase in the risk of death in patients with heart failure and coronary artery disease.51 Similarly, an elevated E/e′ indicates a poor prognosis in a wide variety of patients.23Download figureDownload PowerPointFigure 7. Survival free of hospital admission in 508 patients with EF <35% is reduced in those with E-wave DT <125 m/s. Reproduced from Giannuzzi P, Temporelli PL, Bosimini E, Silva P, Imparato A, Corrá U, Galli M, Giordano A. Independent and incremental prognostic value of Doppler-derived mitral deceleration time of early filling in both symptomatic and asymptomatic patients with left ventricular dysfunction. J Am Coll Cardiol. 1996;28:383–390, copyright © 1996, with permission from Elsevier.ConclusionsComprehensive echocardiographic evaluation, including blood flow Doppler and tissue Doppler, provides essential information in patients with heart failure. In addition to assessing cardiac structure and systolic LV function, the diastolic filling dynamics provide prognostic information and can help guide therapy. Patients with myocardial dysfunction have a reduced and delayed e′, indicating slowed relaxation. An increased E wave in the presence of a reduced e′ (ie, E/e′ >15) indicates elevated LA pressure. In patients with borderline increased E/e′ (>8, <15), the entire echocardiographic picture should be assessed, including LA size, mitral filling pattern, DT, pulmonary vein velocities, and pulmonary artery systolic pressure. This information is particularly helpful in establishing the diagnosis in patients with the clinical picture of heart failure when the LV EF is preserved. It provides prognostic information and can help guide therapy in patients with heart failure regardless of the EF.DisclosuresNone.FootnotesCorrespondence to William C. Little, MD, Cardiology Section, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157–1045. E-mail [email protected] References 1 Little WC. Hypertensive pulmonary oedema is due to diastolic dysfunction. Eur Heart J. 2001; 22: 1961–1964.CrossrefMedlineGoogle Scholar2 Gaasch WH, Little WC. Assessment of left ventricular diastolic function and recognition of diastolic heart failure. Circulation. 2007; 116: 591–593.LinkGoogle Scholar3 Little WC. Diastolic dysfunction beyond distensibility: adverse effects of ventricular dilatation. Circulation. 2005; 112: 2888–2890.LinkGoogle Scholar4 Bell SP, Nyland L, Tischler MD, McNabb M, Granzier H, LeWinter MM. Alterations in the determinants of diastolic suction during pacing tachycardia. Circ Res. 2000; 87: 235–240.CrossrefMedlineGoogle Scholar5 Cheng CP, Freeman GL, Santamore WP, Constantinescu MS, Little WC. Effect of loading conditions, contractile state, and heart rate on early diastolic left ventricular filling in conscious dogs. Circ Res. 1990; 66: 814–823.CrossrefMedlineGoogle Scholar6 Courtois M, Kovacs SJ Jr, Ludbrook PA. Transmitral pressure-flow velocity relation: importance of regional pressure gradients in the left ventricle during diastole. Circulation. 1988; 78: 661–671.CrossrefMedlineGoogle Scholar7 Cheng CP, Noda T, Nozawa T, Little WC. Effect of heart failure on the mech