Cardiac Resynchronization Therapy
John Rickard
I. INTRODUCTION.
The prevalence of heart failure (HF) in the United States has increased considerably in the past two decades as a result of the aging population and better medical management of left ventricular dysfunction (LVD). Unfortunately, medical therapy is not completely effective in preventing or reversing the progression of HF, and as a result, patients with advanced HF have limited options. A subset of patients with systolic LVD who have associated ventricular conduction delay are at highest risk for HF progression and a poor overall outcome. Since the late 1970s, various investigators have shown that left bundle branch block (LBBB), right ventricular (RV) pacing, or intraventricular conduction delay (IVCD) is associated with a less favorable hemodynamic profile in those with LVD and even in normal subjects. The mechanism for this phenomenon is thought to be due to asynchronous and inefficient contraction of opposing areas of the ventricular myocardium. More importantly, restoring synchronization, either via simultaneous pacing of the RV apex and the left ventricular (LV) free wall or with timed LV free wall activation, can lead to a significant hemodynamic improvement. In 1994, two investigators in Europe applied cardiac resynchronization therapy (CRT) in the clinical setting for the first time. Subsequent small observational studies suggested benefit from synchronous pacing. Larger randomized clinical trials confirmed these findings. CRT was first approved for maximally medically managed patients with persistent New York Heart Association (NYHA) class III or IV HF symptoms due to severe LVD associated with prolonged QRS duration. Further randomized studies, powered for mortality, showed a significant survival benefit with CRT or the combination of CRT with a defibrillator (CRT-D). More recently, CRT has been shown to be beneficial in less symptomatic patients. Unfortunately, not all patients who are selected for CRT based on current guidelines respond. Furthermore, some patients who would not be selected for CRT based on the current guidelines may actually benefit from this therapy. One of the major current challenges in this field is the optimal definition of the appropriate and cost-effective use of this expensive technology.
II. MECHANISM OF LV DYSSYNCHRONY.
The normal pattern of electrical activation of the ventricular myocardium, once the impulse passes through the atrioventricular (AV) node, starts in the His bundle, followed by simultaneous activation of the right and left bundles of the Purkinje system and then by myocardial depolarization. The Purkinje system is electrically isolated from the rest of the myocardium until it reaches its exit points at the Purkinje—myocardial junctions. As a result, typical LV myocardial activation occurs from the apex to base, simultaneously in the septum and in the LV free wall, and is described as synchronous. Due to tight electromechanical coupling of the myocardium, synchronous ventricular activation is followed by synchronous ventricular contraction.
In the setting of conduction delay, the electromechanical coupling of the heart is disrupted, leading to dyssynchrony. Over time, electromechanical uncoupling leads to impaired stroke volume, worsened mitral insufficiency, prolonged LV isovolumetric
events, and impaired diastolic filling. These effects contribute to adverse remodeling in the already impaired heart, creating a vicious cycle that perpetuates this process into more advanced HF. As a result, when comparing patients with similar degrees of LVD, those with conduction delay have a worse overall prognosis. CRT has been shown to reverse this deleterious process. Synchronized pacing has been shown to improve LV function without increasing oxygen demand, suggesting that the improvement is related to better efficiency of the LV chamber.
events, and impaired diastolic filling. These effects contribute to adverse remodeling in the already impaired heart, creating a vicious cycle that perpetuates this process into more advanced HF. As a result, when comparing patients with similar degrees of LVD, those with conduction delay have a worse overall prognosis. CRT has been shown to reverse this deleterious process. Synchronized pacing has been shown to improve LV function without increasing oxygen demand, suggesting that the improvement is related to better efficiency of the LV chamber.
Interestingly, dyssynchronous activation and contraction have an undesirable effect in patients without LV systolic dysfunction also. When compared with normal controls, patients with LBBB have a lower ejection fraction (EF), are more likely to develop HF, and have a tenfold greater cardiovascular morbidity and mortality risk. In some patients (patients with chronic LBBB, frequent premature ventricular contractions, or chronic RV pacing), the conduction delay in and of itself may cause deterioration in the EF. In this population, treatment with CRT can have profound effects potentially normalizing the LV function.
III. TYPES OF DYSSYNCHRONY
A. AV dyssynchrony.
In the setting of PR or QRS prolongation, the atrial contribution to LV filling is abnormal. Atrial systole occurs too early with respect to ventricular diastole, leading to early truncation of passive LV filling. Early atrial systole also causes an early rise in diastolic ventricular pressure, leading to diastolic mitral regurgitation (MR). Compromised LV filling and MR cause lower cardiac output. AV synchronization can improve cardiac output in HF by as much as 20%.
B. Interventricular dyssynchrony.
Early RV activation present during LBBB, IVCD, or RV pacing leads to early RV contraction, creating a pressure gradient between the RV and LV that negatively affects LV filling, which translates to a decrease in LV preload and a subsequent decrease in cardiac output. In the early development of CRT, interventricular dyssynchrony was thought to be a major contributor to adverse events in patients with HF and conduction disease. More recently, however, interventricular resynchronization has not been shown to be of significant benefit, clinically calling the role of interventricular dyssynchrony in the failing heart into question.
C. Intraventricular dyssynchrony.
In the presence of conduction delay, there is a substantial delay in the activation of certain LV segments compared with others, leading to an inefficient back-and-forth mechanical interaction that results in inefficient myocardial contraction. In the case of a native LBBB for example, there is a significant delay in activation between the early activated septum and the late activated posterolateral wall, often resulting in profound delays between segments. Mitigation of intraventricular dyssynchrony is currently thought to be the primary mechanism of improved myocardial performance with CRT.
IV. ASSESSMENT OF DYSSYNCHRONY
(see Table 56.1). While CRT has been established as an effective therapy for patients with conduction delay and LVD, approximately 30% of patients meeting current implantation criteria fail to respond (depending on one’s definition of response). This has spawned a major research effort to identify dyssynchronous contraction preimplantation to refine appropriate patient selection for this procedure. In addition to the three varieties of dyssynchrony already discussed, dyssynchrony can also be broken into “mechanical” and “electrical.” Electrical dyssynchrony refers to delays in depolarization from one segment to another, whereas mechanical dyssynchrony refers to contraction delays from one segment to another. While the two are presumed to be closely linked, current measures of electrical and mechanical dyssynchrony have often shown poor agreement. For example, almost all clinical trials have used prolonged QRS duration, a crude marker of electrical dyssynchrony, as a requisite for inclusion. The relationship, however, between QRS duration and various
measures of mechanical dyssynchrony has been poor. Studies have revealed that up to 30% of patients with a prolonged QRS duration do not have mechanical dyssynchrony as assessed by magnetic resonance imaging (MRI) or echocardiography, whereas up to 30% of patients with a normal QRS duration and symptomatic HF have evidence of mechanical dyssynchrony on echo or MRI and could potentially benefit from resynchronization therapy. Currently, the development of new measures of both electrical and mechanical dyssynchrony is an area of intense research. While newer, noninvasive measures of electrical dyssynchrony other than the QRS duration are on the horizon, currently, the bulk of research on dyssynchrony has been dominated by the various metrics of mechanical dyssynchrony, mostly using various echocardiographic techniques.
measures of mechanical dyssynchrony has been poor. Studies have revealed that up to 30% of patients with a prolonged QRS duration do not have mechanical dyssynchrony as assessed by magnetic resonance imaging (MRI) or echocardiography, whereas up to 30% of patients with a normal QRS duration and symptomatic HF have evidence of mechanical dyssynchrony on echo or MRI and could potentially benefit from resynchronization therapy. Currently, the development of new measures of both electrical and mechanical dyssynchrony is an area of intense research. While newer, noninvasive measures of electrical dyssynchrony other than the QRS duration are on the horizon, currently, the bulk of research on dyssynchrony has been dominated by the various metrics of mechanical dyssynchrony, mostly using various echocardiographic techniques.
TABLE 56.1 Commonly Used Echocardiographic Measurements of Dyssynchrony | ||||||||||||||||||||||||
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A. Echocardiographic assessment of dyssynchrony.
The assessment of cardiac mechanical dyssynchrony was initially made with M-mode and pulsed-wave Doppler. Subsequently, tissue Doppler imaging (TDI) and tissue synchronization imaging have been used. More recently, three-dimensional echocardiography and speckle tracking technology have shown considerable promise. The main difficulty with all measures of mechanical dyssynchrony has been reproducibility across centers. In the large, multicenter PROSPECT trial, multiple echocardiographic measures of mechanical dyssynchrony were tested. None, however, were found to be both a sensitive and a specific predictor of subsequent response to CRT. Technical and interpretative variability across centers was thought to be a major reason behind the only modest predictive ability.
1. Pulsed-wave Doppler has been used to assess interventricular dyssynchrony by measuring the time delay between initiation of RV and LV ejection, known as the presystolic ejection period. One advantage of this technique is good feasibility and reproducibility. While values > 40 milliseconds are considered to be abnormal, the clinical utility of this measure remains to be proven.
2. Septal to posterior wall motion delay as assessed by M-mode in the parasternal long or short axis view has been used to detect intraventricular dyssynchrony. A value > 130 milliseconds has been associated with a greater response to CRT in terms of symptomatic improvement, LV remodeling, and EF increase. Advantages include the ability to perform this measure on all echocardiographic systems without the requirement of specialized software. Unfortunately, this parameter has significant limitations. It evaluates dyssynchrony in only two segments of the myocardium: the septum and the posterior wall. Additionally, it may be difficult to obtain in up to 40% of patients due to poor acoustic windows
as one must be perpendicular to the myocardial walls, which is often difficult in patients with low parasternal windows.
as one must be perpendicular to the myocardial walls, which is often difficult in patients with low parasternal windows.
3. Tissue Doppler imaging. This technique uses pulsed-wave Doppler to record myocardial velocities at the basal septum and the basal lateral wall as close as possible to the mitral valve annulus in the four-chamber view. Time from the onset of the QRS to the onset of systolic velocity or to the peak of systolic velocity is measured. So too is the difference in these measurements between the septum and the lateral wall. Values > 62 milliseconds for time to systolic velocity initiation and 65 milliseconds for time to peak systolic velocity are abnormal and have predicted a favorable clinical and echocardiographic response to CRT. TDI has excellent temporal resolution and does not require endocardial border identification for determining the degree of delay. The limitations of TDI are as follows: (1) occasional difficulty in identifying the true peak of systolic velocity and (2) because segments are not assessed simultaneously, heart rate variability and respiration can lead to false comparisons. To better deal with these limitations, computer software has been developed that allows postprocessing of Doppler data so that all of these measurements are determined from one image. Additional views (apical three-chamber and apical two-chamber) may be used to increase the number of myocardial segments assessed. This technique improves both specificity and sensitivity in the identification of mechanical dyssynchrony, as compared with older, less sophisticated methods.
Another major problem with current methods of TDI is that they assess systolic motion only in the longitudinal plane of the heart and, therefore, may be prone to artifact from tethering and pulling. The heart contracts in three different planes: longitudinal, radial, and rotational. The latter two are not assessed by conventional TDI but have a greater contribution to ventricular contraction than the longitudinal plane.
4. Three-dimensional imaging. The development of three-dimensional echocardiographic technology now allows the measurement of endocardial wall motion in reference to a center point. Using computer assistance, the endocardial border is tracked. Only the end-systolic and end-diastolic positions of the ventricular apex and mitral annulus must be determined by the operator. This technique permits the calculation of the three-dimensional dyssynchrony index, which quantifies mechanical dyssynchrony as the standard deviation of the time to minimum systolic volume as a percentage of the cardiac cycle length. While three-dimensional motion delay imaging has shown promise as predictive of subsequent reverse remodeling following CRT, it remains limited by the need for good image quality and a stable heart rhythm.
B. New echocardiographic indices of mechanical dyssynchrony.
Newer echocardiographic techniques focus on eliminating the shortcomings of longitudinal TDI, namely, the tethering and pulling artifact, and lack of radial and rotational strain assessment.
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