The Sonographer Attachment Programme At USA Report : Mayo Clinic: Advanced Echo =Tissue Doppler Imaging I=

TDI Dyssynchrony Study I

Biventricular pacemaker therapy, or cardiac resynchronization therapy (CRT), is rapidly developing device therapy for heart failure. This therapy is unique in that cardiologists from at least three major subspecialities (heart failure, device and echocardiography group) are involved in the management of patients. In fact, echocardiography serves a vital role throughout the management of patient from pre implant assessment to device optimization, evaluation of treatment efficacy and finally to the prediction of a favorable response. Multiple echocardiograpic techniques, especially new echocardiographic technologies are used to assess asynchrony or dyssynchrony of the ventricle or ventricles. Key aspects of the practical use of echocardiography in the CRT era are summarized below.

Systolic Dyssynchrony Of The Ventricle Or Ventricles And Its Implication For Worsening Of Heart Failure.

Systolic mechanical dyssynchrony can be defined as the uncoordinated timing of contraction in different regions of the heart.That is myocardial segmental contractions do not occur simultaneously. Systolic dyssynchrony is commonly manifested as prolongation of the QRS duration on surface electrocardiography (ECG). This prolongation of the QRS duration is a relatively simple marker that indicates the presence of electromechanical coupling delay in the ventricle or ventricles. Morphologically, the prolonged QRS can be manifested in the form of bundle branch block (left or right) or intraventricular conduction delay. QRS prolongation (>120 miliseconds) has been described in one fourth to one half of patients who have heart failure. Systolic dyssynchrony can be divided into intraventricular (within the LV) and interventricular (between the LV and right ventricle dyssynchrony. Intraventricular dyssynchrony results in a fragmented profile of ineffective contraction, with prolongation of the isovolumic contraction and relaxation times. The regional “shifting” rather than ejection of blood from the LV worsens regional wall stress and aggravates mitral regurgitation. These factors, in combination with activation of neurohormonal and proinflammatory cytokine pathways, accelerate cardiac dilatation, resulting in progressive LV dilatation and cardiac remodeling. Interventricular dyssynchrony, especially in the presence of paradoxical septal motion in systole, may adversely affect RV function, further impeding venous return to the LV.                                             

Cardiac Resynchronization Therapy For Heart Failure

CRT is designed to pace different regions of the ventricles simultaneously. Two ventricular pacing leads are implanted: one is implanted by the coronary sinus or epicardial approach at the LV free wall region and the other is implanted by the conventional RV approach at the septum. Currently, CRT is recommended for patients who have advanced heart failure wuth NYHA functional class III or IV, QRS duration more than 130 milliseconds, systolic dysfunction, and LV dilatation and heart failure refractory to optimal medical therapy. The proven benefits of CRT include improvement in heart failure symptoms, exercise capacity, quality of life, heart failure rehospitalization and mortality. Other important and objective indicators of structural and functional benefits with CRT include echocardiographic evidence of LV reverse remodeling and improvement of systolic function.

Patient Selection For Implantation Of CRT

Echocardiography is the first step for confirming and assessing the severity of LV systolic dysfunction, in particular, identifying patients who have a low EF (typically ≥35%) and a dilated LV. Because patient with Left Bundle Branch Block not uncommonly have paradoxical septal motion, the biplane Simpson method is preferred to the M-Mode method for calculating LVEF.

Assessment Of Response To CRT

One of the objective criteria for confirming a favorable response to CRT is the occurrence of LV reverse remodeling, which is characterized by a decrease in LV volume and an increase in LVEF documented with serial echocardiography examinations, typically for 3 to 6 month after CRT. The LV end systolic volume measured with the biplane Simpson method is commonly used as  a quantitative measure of LV reverse remodeling because incorporates the combined  effect of structural regression and stage of improved systolic function. In previous studies, the average decrease in LV end systolic volume after 3 months of CRT has been about 22% and the decrease in LV end diastolic volume has been about 15%. The average gain in LVEF has been about 8%. The decrease in LV end systolic and end diastolic diameters has been observed consistently in large,multicenter clinical trials for CRT.

Optimization Of The Atrioventricular Interval After CRT

About one half of patients with heart failure who have a prolonged QRS duration also have an accompanying first degree atrioventricular (AV) block. AV prolongation places atrial contraction during early systole, allowing for atrial relaxation in late ventricular diastole rather than in ventricular systole. Several adverse consequences arise from this non physiologic timing. The late diastolic decrease in LA pressure mediated by atrial relaxation abolishes the LA to LV pressure gradient, resulting in a shortened diastolic filling interval. In fact, this gradient may reverse, producing diastolic mitral regurgitation. Because the LV loses augmentation of end diastolic pressure from a properly timed atrial contraction, Starling forces are compromised, reducing LV contractility.

AV optimization by Doppler echocardiography seeks to prevent early diastolic atrial contraction, as described above, without producing the other extreme, in which atrial contraction occurs too late, with interruption of atrial ejection by the next ventricular systole. This later situation is un favorable because the full atrial contribution to filling is compromised and atrial contraction against a closed AV valve produces a mark increase in pulmonary venous pressure. In principle, a hemodynamically favorable AV delay should optimize both diastolic filling Ritter or Ishikawa method. Both techniques place the end of the mitral inflow “A” wave at the onset of isovolumic contraction. In the Ritter method, one assumes a constant atrial electromechanical delay regardless of the location in diastole of atrial activation until the AV interval is so short that atrial contraction is truncated by the next ventricular systole. The time difference in atrial electromechanical activation between a long and short AV delay represents the degree of “A” wave truncation at the short AV delay. If this difference is added to the short AV delay, the optimum AV delay has theoretically been achieved. Specifically, a long AV delay (typically 150 milliseconds) is chosen, which gives partial E and A wave fusion without loss of ventricular resynchronization. A short AV delay (typically 50 miliseconds) is chosen, which clearly result in “A” wave truncation. The electromechanical delay at each AV interval represents sum programmed AV interval and the QA interval, or time from QRS onset to the end of the mitral inflow “A” wave.

If the patient has pronounced mitral regurgitation, the Ishikawa method can be attempted. A long AV delay is chosen that results in either diastolic mitral regurgitation or diastasis until isovolumic contraction, when systolic mitral regurgitation commences. The duration of diastolic mitral regurgitation or diastasis is subtracted from the long AV interval, yielding an optimum AV interval that places the end of the atrial filling wave at the onset of isovolumic contraction.

A recent investigation has suggested that the optimum AV delay as defined by the Ritter formula does not work as well as a maximized mitral inflow time velocity integral or duration when compared with invasive indices of systolic function. This observation may result from the diminutive “A” wave in patients with restrictive filling and associated modest differences in”A” wave duration at long and short AV delays. The atrial contribution to filling may als at the higher LV pressure of late diastole. Thus, it is appropriate to consider an “iterative” approach to optimization of diastolic filling, in which an AV interval is chosen that yields the most robust appearing atrial contribution to filling. Optimization of forward cardiac output can also be examined. In this approach, the time velocity integral of forward flow at the LV outflow tract (LVOT) is measured at multiple AV intervals, typically 20 milliseconds apart, and selected to maintain biventricular stimulation. The largest time velocity integral corresponds to the highest stroke volume and presumably the optimum AV delay.

Centers vary in inclination to formally optimize the AV delay after implantation of a biventricular device. Some institutions, including our own, select an empiric AV interval of 100 milliseconds after sensed P wave and perhaps a 50 milliseconds larger AV interval after paced P wave, recognizing that these values are comparable to the values typically derived by echocardiographic AV optimization in randomized trial. Formal AV optimization is generally reserved for nonresponders to CRT. If formal AV optimization is to be performed routinely, it should be repeated in long term follow up because changes in the optimum AV delay over time have been described in a substantial number of patients.

Optimization Of Interventricular Interval After CRT

It has been proposed that sequential biventricular stimulation, in which LV or RV stimulation precedes the other by 20 to 60 milliseconds, may compensate for regional delays in LV activation or suboptimal coronary sinus lead placement during CRT and thereby provide greater LV synchrony than simultaneously biventricular stimulation, in which LV and RV stimulation occur at the same time. Small studies using CRT patient as their own controls have demonstrated improved indices of systolic function or dyssynchrony or both with sequential compared to simultaneously biventricular stimulation. As with AV optimization, centers must decide whether to optimize the VV interval in all CRT recipients or reserve this optimization for non responders. The most common approach to VV optimization involves stroke volume assesstment at the LVOT at various VV offsets typically separated by approximately 20 milliseconds. Although trials of VV optimization have generally optimized the AV interval first, there is some logic to to optimizing the VV interval first because of the potential influence of improved LV synchrony on the diastolic filling period. In either approach, it must be remembered that current devices define the AV interval as the time delay from atrial channel to first ventricular channel. Therefore, when RV first VV offsets are tested, the AV delay must be shortened by a time equal to the VV offset to maintain an unchanged mechanical interval from LA to LV contraction.

The Role Of Echocardiography In Identifying Of CRT

Despite compelling evidence for the benefit of CRT about one third of patients do not have a response to this treatment. This is because ECG is not a sensitive marker for predicting the presence or absence of electrical activation delay in the LV or electromechanical coupling delay. The other contributing factor for the lack of a favorable response to CRT is placement of the LV lead at a suboptimal site where the efficacy of resynchronization therapy is greatly reduced.

Several methods have been used to characterize non responders to CRT, including hemodynamic, clinical and echocardiographic variables. It is important to appreciate that the prevalence of nonresponders is higher (54%) among patients with borderline prolonged QRS duration of 120 to 150 milliseconds than among those (32%) with a severely prolonged QRS duration of more than 150 milliseconds.

Echocardiographic Tools For The Assestment Of Systolic Asynchrony

A few echocardiographic tools have been described for the assesstment of mechanical dyssynchrony in systole. These include the M-Mode measurement of septal to posterior wall delay, Doppler echocardiography for intervenricular mechanical delay, TDI for assesstment of regional delay and calculation of indices of systolic asynchrony based on different models of 2 to 12 LV segments, 3D echocardiography and postprocessing of TDI such as strain, strain rate, displacement mapping and tissue synchronization imaging.

M-Mode Measurement

Parasternal long axis or short axis views of the LV can be used for the M-Mode assesstment of dyssynchrony. The septal to posterior wall motion delay can be calculated by the difference in the time to peak inward movement of the ventricular septum and posterolateral walls. A septal to posterior wall motion delay of 130 milliseconds or more predicts those who are more likely to have improvement with CRT. One potential limitation of this method is that it assesses only the mechanical timing delay between two segments of the ventricle. Another limitation is that if patients have an akinetic septum there is no peak to measure for septal inward motion. M-Mode recording colour TDI of the septum and the posterior wall may make it easier to measure wall motion delay.

Pulse Wave Doppler Measurement

Pulsed wave Doppler measurement at the LVOT and RVOT can provide information about both intraventricular and interventricular dyssynchrony. The aortic preejection time is measured with pulsed wave Doppler echocardiography from the onset of the QRS complex on ECG to the onset of LVOT flow. Whether the onset of the QRS complex or the peak of the R wave is used as a reference point for timing measurements is not important for measurements comparing the difference in time to peak velocity between two or more ventricular segments. However, it is important to use the onset of the QRS complex as the reference point for measuring aortic preejection time because it represents the time from electrical activation to the onset of flow through the LVOT. The aortic preejection time is prolonged in patients who have LV dyssynchrony.

Tissue Doppler Imaging

TDI allows measurement of peak systolic velocity in the ejection phase of different regions of the myocardium. Moreover, systolic dyssynchrony can be assessed by measuring the precise timing of peak systolic velocity in the ejection phase with reference to the beginning of the QRS complex. Integration of this information allows an accurate assesstment of electromechanical coupling and evaluation of interventricular and intraventricular dyssynchrony. Septal to lateral wall delay can be assessed with pulsed wave tissue Doppler measurement of the difference in the ejection phase for the basal septal and basal lateral walls. A timing delay of more than 60 milliseconds has been reported to have some predictive value for CRT responders.

The assessment of multiple segments with TDI has the theoretic advantage of having the capability of examining different patterns of systolic asynchrony, such as those with delay other than septal to lateral wall delay. In this regard, the use of 2D colour coded TDI is advantageous, in which cine loops of multiple views are collected and analyzed objectively offline.

In the six basal, six mid segmental model, the dyssynchrony index is derived by calculating the standard deviation of ejection phase of the 12 LV segments. From the apical four chamber, two chamber and five chamber (or apical long axis views, six basal, six midsegments are obtained in the LV, namely the septal, lateral, anterior, inferior, anteroseptal and posterior segments at both basal and mid levels. The systolic myocardial velocities consist of an isovolumic contraction phase and ejection phase, both of which are positively directed, that is, apically directed. During diastole, it consists of the isovolumic relaxation phase (negative or biphasic profiles), early diastolic relaxation and late diastolic relaxation, which is negatively directed. To calculate the dyssynchrony index, the peak myocardial systolic velocity is identified from 12 segments. To measure the time to peak systolic velocity in the ejection phase of individual segments, use the following rules of thumb:

• Use aortic valve opening and closure markers that superimpose on TDI tracings to guide the identification of the ejection phase (from a Doppler recording of the LVOT or aortic valve in the apical long axis view).

• Measure the time from the onset of the QRS complex to the highest systolic peak during the ejection phase (between aortic valve opening and closure).

• If there are multiple peaks in the ejection phase, use the highest peak.

• If two or more peaks in the ejection phase have the same amplitude in velocity, then choose the earliest peak among those with the same higest velocity.

• If the segment has only a negative peak in the ejection phase or the velocity is so noisy with very low and inconsistent velocities, neglect those particular segments and proceed with the rest of the measurable segments.

• Do not measure ejection phase on the isovolumic contraction phase or isolumic relaxation phase or during post systolic shortening.

The ejection phase SD is calculated as the standard deviation of ejection phase among six basal, six mid LV segments, the larger the value of ejection phase standard deviation, the more severe the systolic asynchrony.

To apply an echocardiographic index of systolic dyssynchrony in clinical practice, it is mandated that a cut off value be identified objectively to determine clinically relevant systolic asynchrony. Furthermore, a variable needs to predict a favorable response with high sensitivity to be incorporated as a screening test or high specificity as a “rule in” test to ascertain the presence of systolic dyssynchrony.

It should be noted, however that there is a large overlap between the ejection phase SD of normal subjects and that of patients with poor LVEF and left bundle branch block. In Mayo Clinic experience, standard deviation of time intervals obtain by strain imaging is more pacific for patients with poor LVEF and left bundle branch block. As a CRT Working Group at Mayo Clinic, there are performing a prospective study of 200 patients undergoing CRT to assess various aspects of his impressive device therapy for those with systolic heart failure. The aim is to provide the most reliable and practical approach for identifying the patients who will benefit drom CRT.

Pacing therapy for inappropriately selected patients could actually result in worsening of mechanical asynchrony.

Mechanical Dyssynchrony In Patients With Heart Failure

LV mechanical dyssynchrony in fact is present in patients with heart failure who have normal QRS duration. This phenomenon was first described with TDI, in which a ejection phase SD value more than 32.6 milliseconds (a cut off values derived from normal population) was identified in 43% of patients with heart failure who had naarow QRS complexes. Two subsequent studies have also reported the presence of intraventricular dyssynchrony in a similar population. The use of TDI or strain to identify systolic dyssynchrony in a population with a narrow QRS complexes may potentially help more patients with heart failure to benefit from CRT. In a recent pilot study, improvement in clinical status, cardiac function, and LV reverse remodeling was observed after CRT in such population.

Assessment Of The Mechanism of Benefit Of CRT By Echocardiography

In patients with heart failure who have a prolonged QRS duration, widespread LV delay has been observed among various LV segments, with a large variation in regional ejection phase. CRT achieved systolic synchronicity by homogenously delaying the time of early contracting segments to a time similar to that of the delayed segments. Therefore, not only was septal to lateral delay abolished, but other patterns of delay were corrected. Furthermore, improvement in regional displacement, strain, and strain rate has been reported. When interventricular dyssynchrony was examined, the septal to RV free wall delay also improved after CRT. The improvement of intraventricular dyssynchrony is probably the main mechanism for mediating the echocardiographic benefit of CRT, which include LV reverse remodeling, improvement in systolic function, reduction of mitral regurgitation, and gain in LV diastolic filling time. Of interest, all the echocardiographic benefits are pacing dependant and with holding pacing results in progressive worsening of these indices. In fact, LV reverse remodeling not only represents a structural benefit of the heart but is also a strong predictor of favorable long term outcome, such as all cause mortality or hospitalization for heart failure (or both). Apart from the predictive outcome, the degree of LV reverse remodeling is related closely to the amount of systolic dyssynchrony before pacing.

Future Perspectives In The Echocardiographic Assessment Of CRT

There is a continuous quest for identifying responders to CRT more accurately in order to decrease the number of no responders and to improve the cost effectiveness of the treatment. In this regard, echocardiography holds promise because it is noninvasive and readily available and serial assessment is harmless to patients with implanted devices. Therefore, echocardiography potentially could be used as an adjunctive measure in patient selection, regardless of QRS duration. It is important that present knowledge be integrated into clinical practice so that prospective clinical trials can be conducted to examine the efficacy of CRT based on the use of established indices of systolic asynchrony in patient who have a wide range of QRS durations. Echocardiographic technology for assessing systolic asynchrony is also evolving, and those that are potentially useful include 3D echocardiography and tissue synchronization imaging. With 3D echocardiography, complete 3D volume rendered data can be captured within a few beats. The time to minimum volume can be determined for each of the 16 segments of the LV. A standard deviation index of these variables can be calculated to assess the degree of intraventricular asynchrony. With the continuous improvement in imaging quality acquisition capability, and the speed and accuracy of off line analysis of systolic asynchrony in multiple segments, 3D echocardiography has a good potential to be applied as a screening tool.

Tissue synchronization imaging allows rapid visual and semi quantitative identification of regional delay in the LV, and automated calculation of the indices of systolic dyssynchrony is possible. This offers the advantage of a color coded display that highlights the areas of the ventricle that have the greatest delay. A potential limitation is that the peak velocity needed for automated calculations can measure incorrectly from the TDI curves. This can be detected by examining the raw TDI curves and ensuring that the tissue synchronization imaging starting and ending brackets on the ECG are correctly located close to the time of aortic valve opening and closure, respectively. The role of other post processing imaging of TDI, such as displacement and strain mapping, remains to be determined.

To be widely accepted clinically, the optimal method for assessing ventricular dyssynchrony should be accurate, not exceedingly time consuming, and widely available, with technology that is or soon will be available in most echocardiography laboratories. Work continues in this field to determine which method of asynchrony assessment will be accepted routinely for selecting patients for CRT.