Author + information
- Karoly Kaszala, MD, PhD∗ ( and )
- Kenneth A. Ellenbogen, MD
- Division of Cardiology, Virginia Commonwealth University School of Medicine, and the McGuire Veterans Affairs Medical Center, Richmond, Virginia
- ↵∗Address for correspondence:
Dr. Karoly Kaszala, Section of Electrophysiology, Department of Medicine, Room 4A104, Hunter Holmes McGuire Veterans Affairs Medical Center, 1201 Broad Rock Boulevard, Richmond, Virginia 230249.
- biventricular pacing
- cardiac resynchronization therapy
- echocardiographic optimization
- heart failure
- hemodynamic optimization
The results of landmark trials have indicated that biventricular pacing is beneficial in heart failure patients with bundle branch block by promoting reverse left ventricular (LV) remodeling, decreasing heart failure symptoms, and improving mortality (1,2). Although most well-selected patients respond to therapy, there is a group of patients (up to 30%) who fail to improve symptomatically or achieve benefit as assessed by LV structural remodeling. Among the many nuances of pacemaker therapy, one particular aspect of device programming has received special attention, especially in nonresponders: optimization of the paced and sensed atrioventricular (AV) delay and right ventricular to LV pacing timing (ventriculoventricular [VV] timing) (3,4). Early invasive hemodynamic and noninvasive echocardiography studies have indicated that inappropriate (too short or too long) AV interval may truncate LV filling and hamper cardiac function (3). Modification of VV timing is an especially attractive feature in cases that the LV lead is positioned in or near a slowly conducting myocardial region and there is delayed effective LV activation from the pacing site. Some form of AV optimization was used in many cardiac resynchronization therapy (CRT) studies including the major mortality trials (echocardiogram or electrogram-guided AV optimization in the CARE-HF (CArdiac REsynchronisation in Heart Failure study) and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trials, respectively [1,2]), although it is unclear how much influence AV optimization played in the outcomes.
Acute hemodynamic response may be assessed by invasive testing or by echocardiography, using pulse Doppler changes in the mitral inflow pattern (AV delay), recording variations in the aortic velocity-time integral (AV or VV timing) or mechanical dyssynchrony by tissue Doppler measurements (VV timing) (5). The challenge with these methods is that there is significant interobserver and intraobserver variability and reproducibility, especially with evaluation of aortic velocity-time integral and tissue Doppler measurements, and its utility has been called into question (6). In clinical practice, another caveat of echocardiogram-guided pacing interval optimization is the highly time consuming and specialized, labor-intensive nature of the evaluation process. Invasive evaluation (e.g., LV pressure change, LV dP/dtmax, arterial blood pressure change) may be performed at implant but at the cost of added risks and serial measurements are not feasible in clinical practice. Other, noninvasive methods, such as electrogram- or electrocardiogram-based approaches, have the limitation of interpolating electrical activity to hemodynamic changes.
It is in this background that Whinnett et al. (7) present in this issue of iJACC the results of the BRAVO (British Randomized Controlled Trial of AV and VV Optimization) trial, a randomized multicenter, crossover study to evaluate clinical outcomes with echocardiogram versus blood pressure–guided optimization of AV and VV delay. The primary study endpoint was changes in peak oxygen consumption on cardiopulmonary exercise testing, which was performed at the end of each 6-month programming period. Additional secondary endpoints included measures of LV dimensions, N-terminal pro–B-type natriuretic peptide, and quality-of-life scores (Short Form-36 version 2, Minnesota Living with Heart Failure Questionnaire). Blood pressure was measured by a beat-to-beat noninvasive digital blood pressure monitor (digital photoplethysmography, Finapres Medical Systems, Enschede, the Netherlands). A total of 401, predominantly New York Heart Association functional class II patients signed up for the study and 250 patients completed the 12-month protocol including both cardiopulmonary exercise testing. There was no significant difference between groups in peak oxygen uptake, minute ventilation/carbon dioxide production slope (an effort independent measure of cardiac function), and exercise duration or other secondary endpoints. The authors conclude noninferiority of blood pressure–based CRT optimization compared with the echocardiogram-based approach. This study is an important step forward because it clearly shows that a less technically demanding modality may achieve similar effects and may result in optimized clinical resource use.
What is the role of AV/VV optimization in the current era? Invasive and noninvasive studies have unequivocally shown that acute hemodynamic changes occur by modifying the AV or VV delay from the optimal sweet spot for that individual patient. Data on long-term clinical benefit of CRT optimization have been less convincing. In fact, the largest randomized, multicenter study (SMART AV [SmartDelay Determined AV Optimization: a comparison to other AV Delay Methods Used in Cardiac Resynchronization Therapy]) comparing fixed AV delay (120 ms) with echocardiogram- or electrogram-guided (proprietary algorithm by Boston Scientific [Natick, Massachusetts]) approach failed to show any difference in structural remodeling or heart failure symptoms (8). The most likely reason for a limited clinical impact, as also corroborated by Whinnett et al. (7), is that in a large percentage of patients (up to 70%) the optimal AV delay falls between 100 and 150 ms, and within a close range of the optimal AV interval there is relatively small variation in cardiac output. Adjustment in VV timing tends to have an even less acute positive impact on overall cardiac function. Thus, in most patients with standard biventricular device indication and programming, the clinical improvement with biventricular pacing is markedly greater than the benefits of additional hemodynamic optimization, and therefore it is difficult to show additional benefit. There is also a population of nonresponders who may have far advanced heart failure status (e.g., too sick) to derive benefit from optimization, regardless of what form of CRT therapy is used.
There are also uncertainties about changes in optimal AV and VV delay over time and utility of frequent reoptimization. Recent studies with devices using proprietary software algorithms to adjust CRT pacing parameters on a continuous basis have shown promising results in improving heart failure outcome (9,10). Looking forward to new technology, one could envision that improved sensor technology could allow the development of a closed-loop system that is based on a physiologic response, such as changes in blood pressure or stroke volume, and the CRT device could auto-adjust pacing configuration (biventricular vs. LV only) or AV and VV delay to further optimize hemodynamics.
Is the proposed technology better or more efficient than the current standard? Blood pressure–based optimization is certainly simpler, but it is also less sensitive to pick up more subtle changes. For example, invasive hemodynamic studies have shown that in some patients contractility may increase (measured by +dP/dtmax) without significant alterations in LV systolic or arterial pulse pressure (4,11). Whether these nuanced hemodynamic changes are clinically significant is unclear. Additionally, with the current iterations of possible pacing configurations brought on by the addition of multisite LV pacing, nonautomated CRT optimization with whatever method is used becomes a Sisyphean task to complete.
In summary, blood pressure–based optimization is noninferior to echocardiogram-based CRT optimization in unselected patients. Whether there is any additional benefit to measurement of AV filling and VV timing using advanced echocardiographic techniques in selected patients cannot be determined from this study. In the current era of CRT device therapy, it is likely that for many, echocardiography will remain the preferred approach for hemodynamic optimization of the nonresponder patient. The authors demonstrate in a convincing fashion that optimization based on noninvasive blood pressure measurements is just as effective, and easier and cheaper, to perform in clinical practice.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Dr. Kaszala has received research support from St. Jude Medical, Boston Scientific, and Medtronic. Dr. Ellenbogen has received honorarium from Medtronic, Boston Scientific, Abbott, and Biotronik; research support from Medtronic and Boston Scientific; has consulted for Medtronic, Boston Scientific, Abbott, and Biotronik; and has served on a data safety monitoring board for Medtronic.
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