Diastolic function assessment by echocardiography: A practical manual for clinical use and future applications

Diastole is an important component of the cardiac cycle, during which time optimum filling of the ventricle determines physiological stroke volume ejected in the succeeding systole. Many factors contribute to optimum ventricular filling including venous return, left atrial filling from the pulmonary circulation, and emptying into the left ventricle. Left ventricular filling is also impacted by the cavity emptying function and also its synchronous function which may suppress early diastolic filling in severe cases of dyssynchrony. Sub‐optimum LA emptying increases cavity pressure, causes enlarged left atrium, unstable myocardial function, and hence atrial arrhythmia, even atrial fibrillation. Patients with clear signs of raised left atrial pressure are usually symptomatic with exertional breathlessness. Doppler echocardiography is an ideal noninvasive investigation for diagnosing raised left atrial pressure as well as following treatment for heart failure. Spectral Doppler based increased E/A, shortened E‐wave deceleration time, increased E/e’, and prolonged atrial flow reversal in the pulmonary veins are all signs of raised left atrial pressure. Left atrial reduced myocardial strain is another correlate of raised cavity pressure (>15 mm Hg). In patients with inconclusive signs of raised left atrial pressure at rest, exercise/stress echocardiography or simply passive leg lifting should identify those with stiff left ventricular which suffers raised filling pressures with increased venous return.

manometers in the LV and in the pulmonary wedge that reflects the LA pressures, with simultaneous recordings obtained to the closest millisecond. Relative changes in chamber pressures can be studied using LV filling velocities, in different diastolic phases, obtained by spectral Doppler echocardiography, which has now become a well-established integral part of cardiac examination in health and disease.
Intra-atrial and intra-ventricular pressure continuously change, in order to maintain optimum cavity circulations; thus, their contribution to the understanding of cardiac function is limited, instead echocardiographers, based on conventional guidelines, rely on LV filling velocities and pulmonary venous flow velocities in assessing different phases of diastolic function. Such approach helps not only assessing intra-cardiac chamber pressure but studying chamber cavity function, compliance, and myocardial function, thus presenting a comprehensive assessment of cardiac physiology in a highly reproducible fashion.
Although very little circulation occurs during the period of diastasis, early LV filling (E-wave) and late LV filling (A-wave) remain the main determinants of cardiac stroke volume. Diastolic events are preceded by an important phase in the cardiac cycle, the isovolumic relaxation time-(IVRT) which is the time interval between aortic valve closure and mitral valve opening, that is, when the two valves are closed and there is no blood entering or exiting the LV.
During IVRT, a number of important events happen which have been shown to predict diastolic patterns; LV pressure declines, and cavity shape change occurs, that is, inward movement of some segments associated with outward movements of others. The latter observations have been shown in normal hearts and get more pronounced with age, therefore, should not always be seen as pathological. 1 Of course, dyssynchrony of cardiac wall motion may worsen in other conditions, for example, hypertension and coronary artery disease and could significantly impact LV filling pattern. IVRT tends to prolong with age, a change that correlates with slow LV relaxation pattern and its effect on cavity filling velocities, become dominantly late diastolic rather than early diastolic. We have previously shown that those changes are closely related to the fall in myocardial early diastolic velocities and increase in late diastolic velocities with age, perhaps due to age-related collagen deposition causing slow relaxation. 2 Similar but rather accelerated changes may happen because of other conditions, for example, pressure overload as systemic hypertension and aortic stenosis, diabetes, and coronary artery disease. 3 With severe abnormal prolongation of ventricular relaxation, particularly if associated with fast heart rate, early diastolic LV filling might be completely suppressed and the LV becomes A filler or of the summation filling pattern with a single filling component starting before the onset of the P-wave of the ECG. The same filling pattern might be seen in prolongation of PR interval, irrespective of its etiology. These conditions limit the blood volume entering the ventricle and consequently the exiting stroke volume resulting in an overall cardiac output that is maintained by fast heart rate. Those patients, if symptomatic, do not respond well to conventional beta blockers treatment and heart rate slowing medications, since the cardiac output is maintained mainly by heart rate rather than by physiological filling volumes. With further deterioration of myocardial function and ventricular compliance, the cavity becomes stiff and diastolic pressures rise, resulting in a perpetual rise of LA/pulmonary capillary wedge pressure, pulmonary venous hypertension, and eventually pulmonary arterial hypertension. Such changes in LV diastolic function have direct impact on LV filling pattern with IVRT becoming very short <40 ms, could be zero in severe cases, dominant early diastolic filling, and suppressed late diastolic filling velocities. In some cases, with slow heart rate, the raised diastolic pressures might appear as flow reversal during diastasis. In addition to these general features of raised filling pressures, critical assessment of Doppler signals and velocities reveals fast acceleration due to significantly raised LA pressure and fast deceleration due to raised LV diastolic pressures, again with severe cases showing E-wave deceleration faster than its acceleration. This pattern is usually described as restrictive filling pattern.
With successful pressure off-loading of the LV and LA, the right ventricular pressures might normalizes and stroke volume increases. It is important to note that none of the abovementioned filling patterns F I G U R E 1 Displays combined LV (red line) and LA pressure (dotted blue) recordings along with LV Spectral Doppler filling velocities (blue line). Note the detailed relationship between the three diastolic phases and their respective pressure and LV cavity filling velocity changes. Yellow line in A displays apical LV pressure is characteristic or consistent with the clinical diagnosis of heart failure (HF) which is a clinical diagnosis rather than echocardiographic diagnosis. Those patterns of diastolic dysfunction reflect the status of left heart function which should be considered in the context of symptoms, with the restrictive filling pattern, short IVRT, dominant E-wave, and E/A ratio >2.0 as an unstable condition that needs serious pressure relieving medications, in order to avoid the risk of ventricular arrhythmias, which could be life-threatening. With progressive collagen deposition in the myocardium, 5th decade of life, cavity relaxation becomes slower and delayed. This results in prolongation of IVRT and delayed opening of the mitral valve. These changes incur on the overall diastolic period but mainly the early diastolic phase ( Figure 1B) and results in compromised early filling component (or volume) with a compensatory increase in the late diastolic filling and more pronounced apical untwist that results in the E/A ratio to be consistently <1.0. Reversal of E/A ratio to become >1.5 in individuals above 60 years of age should be taken as an indication for diastolic dysfunction with increased LV and LA diastolic pressures, Figure 3.
The above age-related changes worsen and become faster if there is additional pathology affecting the LV, for example, coronary artery disease, valvular disease, cardiomyopathy, or systemic hypertension. In some patients, the early diastolic filling could be completely truncated and the LV fills with an isolated late diastolic component, commonly seen with LV dyssynchrony, as mentioned above. If such patients develop atrial fibrillation, the isolated late diastolic filling component will be shifted to early diastole but on the expense of raising the LA pressure, postcapillary pulmonary hypertension, and reduced stroke volume.

F I G U R E 2
Apical untwist and mitral inflow in young (left) and elderly (right) healthy subjects. Note the time difference of onset of untwist (end systole, blue line) and onset of E-wave (after T-wave, green line) in both subjects. This might be part of mechanism behind suction effect

| Electrical disease
Diastolic phases are also influenced by the electrical pattern of LV activation (depolarization) and repolarization. QRS broadening, irrespective of bundle branch block (BBB), is associated with delayed activation and delayed septal inward motion, which consequently is reflected in delayed segmental outward motion with post-ejection shortening, the combination of the two results in delayed onset and shortened early diastolic LV filling. 4 The same pattern is seen in individuals with absent septal Q-wave 5 and patients with coronary artery disease, particularly those with Q-wave infarction. 6 LV filling pattern could also be affected by other arrhythmia and conduction abnormalities, an absent P-wave, for example, atrial fibrillation results in absent late diastolic filling component, which compromises overall LV filling and stroke volume. Patients with severe LV disease and broad QRS may also develop prolonged PR interval. The combination of the two electrical disturbances may result in long mitral regurgitation with pre-systolic component which shortens filling and reduces stroke volume, particularly with fast heart rate. If these patients do not respond to heart rate slowing medications, they should benefit from DDD pacing with short A-V delay.

| Coronary artery disease
The most sensitive myocardial layer to coronary artery disease and ischemia is the subendocardium, even in patients with no obstructive lesions in the epicardial vessels. Early subendocardial dysfunction has been shown to be predominantly diastolic, and as it worsens, it becomes systolic. Disturbances are similar to those described above, but the delayed segmental shortening and lengthening is more profound and reverse after revascularization, 7 particularly in patients with no additional electric disease. 8 In those with a prior infarction, the scarred myocardial segment might be dyssynchronous and hence adds to the extent of filling abnormalities. In severe cases and with more than one dyssynchronous segment, the LV cavity might fill with an isolated late diastolic component. Specific patterns of myocardial incoordination have been described, with inferior infarcts causing global LV segmental dyssynchrony because of the papillary muscle blood supply being from the right coronary artery and even more aggressive form of global incoordination that contributes to subendocardial ischemia at rest in patients with unstable angina. 6,9 1.2 | Heart failure and diastolic function

| Heart failure symptoms
The main symptom of HF is breathlessness and fatigue. If cardiac dysfunction is the prime cause of symptoms, it is likely to be caused by either impaired emptying of the LA due to early diastolic dysfunction (relaxation disturbances, Figure 1B) or due to raised LA pressure (restrictive filling pattern, Figure 1C) as a complication to raised LV end-diastolic pressure. The latter has clear characteristics: dominant early diastolic component, short IVRT, reduced and delayed apical early diastolic untwist 10

| Heart failure signs
A third heart sound, heard in a HF patient, is consistent with restrictive LV filling ( Figure 1C) and is caused because of rapid turn of early diastolic filling acceleration into deceleration. This condition reflects unstable cardiac function that needs LA pressure off-loading therapy with vasodilators. The fall in LV pre-and afterload results in consequent drop in LA pressure and normalization of LV filling pattern which unmasks the original underlying diastolic function abnormalities, in most cases dyssynchronous patterns become apparent and influence LV filling ( Figure 1B,C), as described above.
Such change in LV filling should be a treatment objective, while increasing the vasodilators doses, in order to stabilize LA function and avoid arrhythmias. A fourth heart sound, in most cases, reflects isolated late diastolic filling due to severe early diastolic dyssynchrony. Signs of pulmonary edema reflect raised LA pressure, which is again, secondary to stiff LV and raised end-diastolic pressure.
Most patients with HF present with some degree of mitral regurgitation, which further accentuates LA pressure and post-capillary pulmonary hypertension. Systemic fluid retention is a sign of either stiff right ventricle or significant tricuspid regurgitation, secondary to left heart disturbances and post-capillary PH or due to primary right heart problems with/without pulmonary hypertension. 11,12

| Guidelines based assessment of diastolic function
Guidelines recommend grading diastolic function into four categories; normal, slow relaxation, pseudo-normalized, and restrictive filling pattern. 13 While the first two categories suggest normal filling pressures, the third and fourth patterns are consistent with raised filling pressures, although to different severities. Invasive assessment of filling pressures itself could be clinically confusing, with some studies using LV end-diastolic pressure, 14  Relaxation abnormalities can also impact LV filling, in the presence of normal filling pressures. This condition is characterized by reduced E-wave velocity, increased A-wave velocity, E/A <0.8, prolonged E-wave deceleration time (>200 ms), and IVRT >100 ms Such pattern is commonly seen in the healthy elderly above 60 years and therefore has low sensitivity in detecting heart failure ( Figure 1B). However, if associated with an enlarged LA (volume > 34 mL/m 2 ), it raises strong suspicion of unstable LA pressures and an exercise provocation such as exercise echo or passive leg lifting can be useful in order to confirm raised LA pressure as shown by increase in E/A, E/e', and TR velocity and unchanged stroke volume Table 1. 19 Resting Doppler echocardiographic measures of diastolic function and their existing discrepancies create significant limitation, mainly because of heart rate impact on time relations and the commonly seen arrhythmias. Such limitation highlights the need for using more than one parameter before drawing a clinical conclusion.
A short IVRT as the interval between the end of the aortic Doppler velocity signal and the onset of the E-wave is also a good reflection of raised LA pressure. A short transmitral E-wave deceleration time is a good marker of raised LV end-diastolic pressure but not always that reproducible, particularly in patients with atrial fibrillation. A The increase in heart rate with exercise stress accentuates venous return which raises LV and LA pressures in patients with stiff and noncompliant LV. Such increase in LV and LA pressures has its consequences in the form of pulmonary venous hypertension, pulmonary hypertension, and clinical symptoms of shortness of breath. Similar pathophysiological findings have been shown by simple leg lifting at rest. 26,27 Stress echocardiography has also been shown to play an important prognostic role in such patients and in showing better clinical outcome in patients with restrictive filling pattern who convert into nonrestrictive filling pattern at fast heart rate which is consistent the presence of significant myocardial diastolic reserve, 28,29 compared with those who remain with restrictive filling. 30

| Diastolic function measurements in HFpEF
Heart failure with preserved ejection fraction (HFpEF) has no specific characteristic pattern of diastolic function. All patterns described above apply to HFpEF, in particular LA enlargement. In addition, an E/A >1.5 in an elderly patient (>60 years) 31 is highly suggestive of elevated filling pressures.
The only difference might be the disproportionate small volume of the LA with respect to the poor LV myocardial function might be in patients with ATTR amyloid heart disease, in whom the LA could be just slightly enlarged, due to atrial myocardial infiltration, Figure 4. 32 However, others have not found the same pattern of left atrial morphology in cardiac amyloidosis. 33

| Diastolic function in fast heart rate
It is very important not to apply the absolute values of diastolic function parameters in patients with HF when presenting with tachycardia. Since heart rate affects diastole before it affects systole and all diastolic intervals become shorter, this behavior is the opposite of what treatment with beta blockers does in optimizing diastolic function and increasing stroke volume. With fast heart rate, diastasis becomes minimal making the two filling components close until they eventually merge and become one summation filling component.
Therefore, correcting all time intervals to heart rate is strongly advis- able. An example of such approach is the assessment of total isovolumic time, which is the product of subtracting the sum of the filling time and ejection times from RR interval and correcting it for heart rate. This gives a value in s/m. It is simple and highly reproducible. It has also been shown to be very accurate in assessing the presence and severity of LV dyssynchrony in HF. 31 Furthermore, LV filling time can be measured and indexed to RR, a simple measure which normally should not reduce by more than 40% at peak exercise.

| Diastolic function and ventricular interaction
Ventricular interactions are known as a hemodynamic phenomenon since Bernheim. 34 However, in primary RV disease such as pressure overload (pre-capillary PH) or RV volume overload, the overload creates a septal shift as well as suppressed LV filling volume. Commonly in both conditions, a reduced LV E/A is expected, a finding that indeed has a significant prognostic value. 35

| Left atrial myocardial function in assessing raised cavity pressure
The recently developed speckle tracking based assessment of LV myocardial deformation technique has been implemented also for the LA. Studies have shown that LA myocardial strain and strain rate play important role in estimating cavity pressure and in predicting response to myocardial arrhythmia, Figure 5. 36,37 Indeed, a recently published meta-analysis showed that LA systolic strain <19% is a very accurate marker for estimating raised pulmonary capillary wedge pressure of >15 mm Hg. 38 Interestingly, the same value has been shown in another meta-analysis to predict successful response to atrial fibrillation ablation. 39 Such measurements are easy to obtain although may slightly differ between vendors.

| Diastolic function and passive leg lifting
Vasalva maneuver has been proposed to test the ability of LV to reduce filling pressures through decreasing preload, i.e. reduced E/A with Vasalva indicates reversible restrictive LV. However, accuracy in having the pulsed Doppler sample volume placed at the same region is very difficult as the LV geometry changes while reducing preload and image quality reduces too. Therefore, and inverse Valsalva manouever with preload increase might be beneficial in providing such information. Along with the concept of increasing venous return with stress/exercise as means for assessing pathological rise of LA pressure as an explanation of exertional breathlessness, simple passive leg lifting ( Figure 4) has been recently proposed to achieve similar objective. We have found PLL together with NT-pro-BNP useful in identifying HF patients with increased PCWP >25 mm Hg during supine exercise. 26 We tested PLL and echocardiography in 29 patients with HF symptoms but normal resting PCWP based on invasive pressure recording. Resting measures of LA volume and strain rate during atrial contraction predicted unstable PCWP (>15 mm Hg during PLL). Furthermore, the latter measured during PLL correlated well with PCWP during PLL. 27 Such simple procedure should be eas- ily used in open access HF clinics for fast and accurate stratification of patients for optimum management ( Figure 6). Example of the use of echocardiography in indicating raised LV filling pressures during PLL is shown in Figure 7.  during supine exercise is shown in Figure 8.
Despite that, a number of technical limitations in using exercise/ stress echo still remain, especially with fast heart rate and breathing disturbances. To avoid such limitations, a moderate exercise test at F I G U R E 6 Passive leg lifting F I G U R E 7 Upper resting measures of E/A, e' TR peak velocity, and LV VTI. Lower same measures during passive leg lifting a heart rate of 100-120 beat per minute could suffice the development of disturbances enough to support the diagnosis of raised LV filling pressures that is responsible for symptoms. 43 A diagnostic algorithm for identifying patients with elevated left ventricular filling pressures at rest and during cardiac stress is shown in Figure 9.