Potential Limitations and Future Research

A major clinical application of echocardiography is the assessment of left ventricular function.

This is a fundamental part of the standard echocardiographic examination, but is especially important in patients with heart failure and post-myocardial infarction .Two-dimensional (2D) and Doppler echocardiography plays important roles in the diagnosis, management, and risk stratification of patients with systolic dysfunction. Assessment of LV size is one of the most

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important components of quantitation of ventricular function. Qualitative and quantitative data derived from echocardiography, e.g., LV dimensions and wall thickness, can influence patient management and serve as potent predictors of outcomes.

LV dimensions by m-mode⁸⁷

The oldest and still widely used method for linear measurements of LV size is M-mode echocardiography. It is simple, reproducible, accurate (when properly applied), and provides excellent endocardial border definition (owing to high frame rate). The American Society of Echocardiography (ASE) recommends measurement of LV dimensions with the M-mode line perpendicular to the long axis of the heart and immediately distal to the tips of the mitral valve leaflets in the parasternal long axis view. Measurements are taken at end-diastole (d)—defined as the beginning of the QRS complex—but preferably using the at the widest LV cavity diameter, and at endsystole (s)—using the narrowest LV cavity diameter. The leading-edge convention of the ASE is the recommended method of measurement. The diastolic measurements obtained are the interventricular septal wall thickness, the LV internal diameter at end diastole (LVIDd) and posterior wall thickness. In systole, the LV systolic diameter (LVIDs) is measured.Calculations of other indices of LV systolic function, e.g., LV ejection fraction (EF), volumes, and mass can then be performed.

A common pitfall of M-mode measurements is the non-perpendicular alignment of the M-mode line in relation to the long axis of the LV. This leads to overestimation ventricular dimensions.

Two-dimensional (2D)-guided M-mode measurements can aid proper alignment thereby minimizing error. Another challenge is to accurately identify the endocardial and epicardial borders and avoid confusion with contiguous structures, e.g., chordae, trabeculations near the

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posterior wall, and false-tendons. The endocardial border is distinguished from ventricular trabeculations and chordae by appearance as a continuous line of reflection throughout the cardiac cycle. The latter structures appear intermittently. The epicardium lies just anterior to the highly echo-reflective parietal pericardium. A major drawback of M-mode measurements is that these are valid only when LV geometry is normal. When LV geometry is abnormal as in aneurysmal remodelling or in the presence of regional wall motion abnormality following myocardial infarction, M-mode measurements of heart size may be misleading. An exponential relationship exists between ventricular diameters and ventricular volumes. M-mode parameters, and indeed all other parameters of LV systolic function, are dependent on ventricular loading conditions.

Two-dimensional-guided M-mode measurements and derived indices⁸⁷. M-mode is simple, reproducible, and accurate when ventricular geometry is normal. It provides good endocardial resolution. The ejection fraction (EF, Teich) is an automated calculation based on the Teichholz method.

Assessment of global left ventricle systolic function⁸⁸

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Echocardiography as a modality to measure LV function may not be very close to ideal.

Maximum rate of change of pressure (dP/dt max) during the systole may be an appropriate measure but this requires an intramyocardial or intracavity micromanometer, and since these laboratory modalities cannot be used routinely in clinical scenario, less invasive or non-invasive techniques which measure a mean pressure change or a change in volume or other surrogates of volume become handy for routine use.

Global LV systolic function can be indirectly assessed by echocardiography using the following indications:

 Changes in LV volume or LV dimension, including cardiac output (CO)

 Systolic index of contractility (dP/dt)

 Global longitudinal strain (GLS) with speckle tracking echocardiography (STE).

Assessment of changes in the left ventricle volumes and dimensions⁸⁷

Dimensions as a surrogate of volume are easy to measure but would be accurate in cases of measurable geometric shapes. The LV does not conform to any ideal geometric shape and so calculations based on any assumption of shape will not be absolutely true. 2D echocardiography, 2D-guided M-mode echocardiography, and Doppler echocardiography are used to measure the dimensions and volume of LV cavity. Recommendation for the measurements using M-mode is from the leading edge to leading edge while that for 2D is from trailing edge to leading edge.

The 2015 ASE/ESCI guidelines states that “the same range of normal values for LV and RV chamber dimensions and volumes apply for both TEE and TTE” .

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Global LV function can be assessed using changes in the LV dimensions and volumes between LV diastole and systole. The recommended calculations are as follows: Fractional shortening (FS), Fractional area change (FAC), Ejection fraction (EF), Stroke volume (SV) and CO.

Fractional shortening⁸⁹

In 2D echocardiography, the measurement of LV diameter taken just below or at the tip of the mitral valve leaflets in the parasternal long axis view or LV diameter taken exactly through the centre point of the LV cavity in parasternal short axis views, either basal or mid-papillary level, during diastole and systole will help to calculate FS of LV at that plane by the following equation.

FS = LVIDd – LVIDs/LVIDd × 100%.

Where, LVIDd = LV internal diameter at end diastole and LVIDs = LV internal diameter at end systole. In M-mode echocardiography, aligning M-mode cursor just at the tip of mitral leaflets or exactly perpendicular to the inferior wall and passing through the center of the LV cavity will give us a M-mode trace, and these measurements can be timed more accurate. Since mechanical systole lags behind the electrical systole, the measurement of LV dimension when the time cursor is placed at or immediately before the peak of the R-wave in QRS complex is considered as LVIDd, and the LV dimension at the end of T-wave in electrocardiogram (ECG) is taken for LVIDs. This is applicable for all 2D and M-mode measurements.The limitation is that FS measures myocardial function in just one plane and do not represent global LV shortening in the presence of regional wall motion abnormalities (RWMA). Measurements are greatly influenced by preload and afterload of LV.

xlv Left ventricular ejection fraction⁸⁹

Left ventricular ejection fraction (LVEF) represents SV as a percentage of end-diastolic volume.

LVEF = LVSV/LVEDV × 100% = (LVEDV − LVESV)/LVEDV × 100%.

Where, LVSV - left ventricular SV, LVEDV - left ventricular end-diastolic volume, LVESV - left ventricular end-systolic volume.

2D echocardiography employs tomographic image acquisition and is depicted in a single plane.

Calculation of volume which is a 3-dimensional from 2-dimensional image requires mathematical calculations based on geometric models. LV volume has been calculated using many geometrical shapes, and they have undergone rigorous validation studies. Calculations based on shapes such as prolate ellipsoid, truncated ellipsoid, and area length methods worked only in normally shaped and sized ventricles but all failed in clinical use with abnormal ventricles. Biplane method of multiple discs (Simpson's) fared well even with abnormal ventricles. Teichholz method (based on simple ellipsoid shape with a correction factor) and prolate ellipsoid method (which uses a simplified cube formula rather than the nonsimplified prolate ellipsoid equation) are all based on a single linear measurement of LV cavity made using M-mode echocardiography cursor placed perpendicular to LAX of LV at the tip of the mitral valve in a parasternal Long axis view.

Cardiac output and cardiac index⁸⁹

2D and Doppler echocardiography modalities can be used to calculate CO using the following formula:

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 SV = CSA × VTI (velocity time integral [VTI])

 CO = SV × HR (heart rate [HR])

 Cardiac index (CI) = CO/BSA (body surface area [BSA]).

Ideally, the CSA of the outflow, where SV is measured, should not change during the whole period of systole, the flow profile through that outflow should have a flat velocity profile and a laminar flow, alignment of Doppler beam should be parallel to and through the center of the blood flow column, and the measurements of CSA and VTI are made at the same anatomical site. Left ventricular outflow tract (LVOT) is usually considered for both the measurements. VTI is calculated from the spectral display of the pulsed wave Doppler (PWD) with its sample volume in LVOT just below the aortic valve. VTI represents the height of the column of blood which has passed through that area where the sample volume of PWD is positioned during systole of one cardiac cycle. CO is such a variable measurement that HR, afterload, and preload of LV will affect it in addition to the LV contractility. There are differences between sex, height, and weight as well. Indexing it to BSA would standardize it to a certain extent and then it is called cardiac index.

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Stroke volume by Doppler (LVOT), and velocity time integral (VTI) ⁸⁸

Systolic index of contractility (DP/DT)⁸⁸

The maximum rate of rise of LV pressure during the isovolumic contraction phase of LV systole, dP/dt(max), is a good measure of LV contractility. This is not affected by afterload and very minimally influenced by preload. The prerequisite for this measurement using 2D and Doppler echocardiography is that the associated mitral valve should have some degree of central mitral valve regurgitation (MR). In that case, the shape of the MR jet, which should be interrogated with a continuous wave Doppler (CWD) and the spectral display optimized, reflects the instantaneous pressure difference between the LV and LA during LV systole. In the presence of global LV dysfunction, the LV pressure build up will decrease and the LA pressure will increase which will decrease the rate of rise of MR jet velocity. This is the principle behind this method of assessing global LV function. Time taken for the velocity to rise from 1 m/s to 3 m/s is measured, and using the modified Bernoulli equation, dP/dt is calculated. The limitation of this method is that a good MR signal is mandatory which may not always be the case. Even eccentric

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jets which will not be optimally aligned to the CWD are of no use. This method is inappropriate in the presence of acute MR because of high left atrial pressures in acute MR. DP/DT is not an entirely load-independent index of LV function.

Color Doppler recording of an eccentric mitral regurgitation and Example of MR dP/dt measurement using CWD⁸⁸

Tissue Doppler imaging for LV function assessment⁹⁰

Tissue Doppler (TD) uses the same principle of pulse wave Doppler (PWD) and its derivative the color flow Doppler. Here, the high-velocity low-amplitude signals from red blood cells are eliminated to display only the low-velocity high-amplitude signals from the myocardium. Main drawbacks are the limitations of PWD, i.e., angle dependency and its inability to differentiate the velocity generated by actual myocardial contraction and that produced by translational motion by akinetic myocardial segments when they get pulled by the adjacent normally contracting myocardium. TD imaging with the PWD sample volume placed at the lateral mitral annuls shows characteristic velocity waveforms with two initial negative and two late positive velocity waves which are named S1, S2, E', and A’ which correspond, respectively, to LV isovolumic, contraction velocity, peak systolic contraction velocity, peak early myocardial relaxation velocity, and late diastolic velocity. Velocity toward transducer is depicted as positive and velocity away from the transducer is depicted as negative. Peak systolic contraction velocity or

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the peak mitral annular descend velocity (PMADV) correlates well with global LV function even though it is very much preload-dependent. Studies have shown that a single, lateral mitral annular PMADV of >5.4 cm/s correlates with an EF of >50% with 89% sensitivity and 85%

specificity.

Tissue Doppler imaging of lateral mitral annulus. Note E’ velocity of >5.4 cm/s suggesting a good left ventricle function⁹⁰

Speckle tracking and global longitudinal systolic strain⁹¹

The ASE/EACVI 2015 guidelines have recommended Global Longitudinal Systolic Strain (GLS) as a reliable and reproducible index of global LV systolic function.

Strain and strain rate: When force is applied on a deformable system, different points in the system move at different velocities resulting in deformation. Strain (ε) is the ratio of the difference between the final length (L) and the initial length (L0) to that of the initial length after the application of the force for a time duration of Δt. That is, ε = L – L0/L0.

The rate at which this happens is the Strain Rate (SR), i.e., SR = ε/Δt.

Now, it is obvious that if the distance between two points, moving at different velocities, is shortened, the strain will be a negative (−) value, and if it lengthens, strain will be a positive value. Extrapolating it to the LV myocardium, contraction is the force and the deformation that

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happens in the LV myocardium is shortening from apex to the base, shortening of the circumference, and lengthening or radial thickening of the LV walls. This is due to the three types of myocardial fibers in the heart; longitudinal, circumferential, and radial myocardial fibers. Thus, longitudinal and circumferential strain will be a negative value while the radial strain will be a positive value. The value of SR comes in a scenario of ischemia-induced regional wall motion abnormality. Ischemic region may be akinetic or have varying degrees of hypokinesia. If hypokinetic, the ischemic region would also reach a final length as a normal myocardium but after a longer period of time. Here, strain in these two areas will be the same, but the rate at which this happens will be slower in the ischemic region, i.e., time to peak strain is increased in ischemic segments.

Angle between the direction of movement of myocardium and that of the ultrasound beam is a great hurdle in Doppler-based techniques of LV function assessment. This is overcome by the technique of speckle tracking and has been validated thoroughly in TTE. Prerequisites for a speckle tracking echocardiography (STE) are good-quality 2D image, preferably a harmonic mode image with a higher frame rate, regular and constant HR with clear ECG trace, and properly timed aortic valve closure. One major issue with STE is the intervendor and inter-software variability of normal values, especially for the circumferential and radial strain even though there has been a consensus and understanding for the peak global longitudinal systolic strain. Age and loading conditions also have an effect on these values.

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Doppler strain imaging showing normal synchronous tissue Doppler tracings of three interrogated myocardial segments⁹¹

Mitral annular plane systolic excursion⁹²

Mitral annular plane systolic excursion (MAPSE) which measures the lateral mitral annular movement toward the apex during LV systole is a surrogate of the left ventricular longitudinal function. Measurements are done with M-mode beam positioned on the lateral mitral annulus, in line with the left ventricular LAX. Maximal systolic plane excursion of the lateral mitral annulus is measured from the M-mode trace. MAPSE is easy to acquire and is more or less accurate. This is an easily reproducible and clinically useful measure of the global systolic left ventricular function. Normal values are usually more than 8 mm with an acceptable range of 12 ± 2 mm. It has some limitations and it requires the lateral mitral annulus to move in the same plane of the M-mode cursor.

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The Vertical distance between the point of the annular most distant from the apex and the point closest to the apex is measured in M mode⁹²

Left ventricular outflow tract ejection acceleration⁹³

In the absence of a significant AV disease, the time taken by the blood column to accelerate and reach the peak velocity through the LVOT is inversely related to the contractile function of the LV. With a PWD sample volume positioned in LVOT in the apical 5-chamber or 3-chamber view, the spectral Doppler will display the LVOT ejection curve which can give information regarding the LVOT peak velocity (Vmax) and LVOT acceleration time (ACT), i.e., the time from the beginning to the peak, and this provides information about global LV systolic function in the form of LVOT ACC. LVOT ACC is calculated as follows:

LVOT ACC (m/s²) = Vmax (m/s)/ACT (s).

When systolic function is normal, the LV ejection curve resembles a sharp-angled triangle. With impaired left ventricular function, the ejection curve becomes flattened and rounded, i.e., with a decreased peak velocity and an increased ACT. LVOT ACC is quite sensitive to global LV

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function and is not load-dependent. Normal range: 8–14 m/s². Limitations are that this method is based on the measurement of a relatively short period of time that may be difficult and even misleading at times. Sometimes, it may be difficult to determine the peak velocity in a rounded velocity curve with no pronounced peak.

LVOT acceleration time measurement⁹³

Myocardial performance index (Tei index)⁹⁴

The myocardial performance index (MPI) is a Doppler-derived integrated measure of ventricular systolic and diastolic function. It has been the subject of much interest since its inception in 1995, and has been well received for its ability to assess both LV and RV function in a variety of patients—heart failure, cardiomyopathy, coronary heart disease, heart transplantation, and in prospective clinical trials. It is reproducible, easy to measure and can predict morbidity and mortality in patients with cardiomyopathy and heart failure. When applied to the LV, it is the sum of the isovolumic contraction and relaxation times (ICT + IRT) divided by the ejection time.

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These measurements are obtained by Doppler assessment of both LV inflow and outflow and using the formula:

Left Ventricular MPI = (ICT + IRT)/ET

The MPI has its limitations. It is not a load-independent measure, and one of its components, the IRT, is less discriminatory in patients with worsening diastolic dysfunction. Therefore, despite its utility, it should complement (not substitute) established measures of LV function, e.g., ventricular volumes and EF.

Myocardial infarction (Tei) index⁹⁴

A) Measurement of Tei index using pulsed-wave Doppler echocardiography (B) Measurement of Tei index using tissue Doppler echocardiography⁹⁴.

lv Diastolic function⁹⁵

Virtually every echocardiographic technique has been used to evaluate diastolic function. This aspect of the left ventricle is clearly more complicated than the systolic function. In the absence of mitral valve disease, abnormal left ventricular diastolic relaxation may cause abnormal motion patterns of the anterior mitral valve leaflet on M-mode echocardiography. Because of impaired relaxation in early diastole, left atrial emptying during the rapid filling period is delayed with resultant decrease in the E-F slope. Atrial contribution to left ventricular filling is increased so that a forceful atrial contraction may cause an exaggerated A-point on M-mode recordings of the mitral valve. The amplitude of excursion of the anterior mitral leaflet during atrial contraction may exceed the amplitude achieved in early diastole during the E-point. Abnormal diastolic relaxation frequently causes significant elevation of left ventricular pressure at end-diastole, which tends to interrupt trans-mitral flow in late diastole with partial closure of the mitral valve before ventricular contraction. This may cause a characteristic pattern on the M-mode tracing whereby a small notch is observed on the anterior mitral leaflet recording (B notch) immediately before its closure.

M-mode echocardiogram,shows increased E-point septal separation and the interrupted closure(B bump) of the mitral valve consistent with elevated end-diastolic pressure⁹⁵.

lvi Mitral valve inflow⁹⁶

Diastole has been traditionally divided into the isovolumic relaxation phase and the filling phase.

The latter is divided into the early filling phase, diastasis and period of atrial systole .The early inflow of blood reaches a peak at the E point. Flow then decelerates until atrial systole at which time the left atrial pressure rises above the left ventricular pressure and blood again passes through the mitral valve. Alterations in the LV diastolic function may reduce the height of the E wave and increase the height of the A wave. This type of abnormality is usually accompanied by prolongation of the isovolumetric relaxation time and prolongation of the deceleration time of the E wave. Reduced left ventricular relaxation is the haemodynamic abnormality responsible for this pattern as well as the slower fall in left ventricular pressure. Left ventricular hypertrophy, cardiomyopathy, myocardial ischemia, and normal ageing are recognized causes of impaired left ventricular relaxation. Atrial contraction occurs with an incompletely empty left atrium and blood is propelled into the left ventricle with increased velocity accounting for the heightened A wave. This pattern can also be seen with a decrease in the filling pressure of the left ventricle as in hypovolemia, dehydration, pulmonary hypertension and systemic vasodilatation. The reverse situation in which the E wave is very tall relative to the A wave with a short isovolumic relaxation time and deceleration time is produced by elevated filling pressure due to reduced compliance or congestive cardiac failure, mitral valve regurgitation, restrictive or constrictive left ventricular disease. With elevated early diastolic pressures, the flow into the left ventricle is accelerated and there may be relatively little blood to be propelled during atrial systole. In restrictive diseases, the initial rapid drop in left ventricular pressure is such that the pressure gradient between left atrium and left ventricle is high producing rapid flow into the left ventricle.

The restriction however causes left ventricular pressure to rebound rapidly and flow into the left

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ventricle to stop abruptly.The same restriction limits atrial filling of the left ventricle any further and the A wave is diminished.

Schematic representation of different component of mitral valve inflow; DT-deceleration time; IVCT- Isovolumic contraction time; IVCT- Isovolumic relaxation time; LVOT- left ventricular outflow tract⁹⁵

Tissue Doppler annular early and late diastolic velocities⁹⁶

PW tissue Doppler imaging (DTI) is performed in the apical views to acquire mitral annular velocities. The sample volume should be positioned at or 1 cm within the septal and lateral insertion sites of the mitral leaflets and adjusted as necessary (usually 5-10 mm) to cover the longitudinal excursion of the mitral annulus in both systole and diastole. Primary measurements include the systolic (S), early diastolic, and late diastolic velocities. The early diastolic annular velocity has been expressed as e¹ and the late diastolic velocity as a¹. Once mitral flow, annular velocities, and time intervals are acquired, it is possible to compute additional time intervals and ratios. The ratios include annular e¹/a¹ and the mitral inflow E velocity to tissue Doppler e=