Animal Models of Dyssynchrony
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Cardiac resynchronization therapy (CRT) is an important therapy for patients with heart failure and conduction pathology, but the benefits are heterogeneous between patients and approximately a third of patients do not show signs of clinical or echocardiographic response. This calls for a better understanding of the underlying conduction disease and resynchronization. In this review, we discuss to what extent established and novel animal models can help to better understand the pathophysiology of dyssynchrony and the benefits of CRT.
KeywordsLeft bundle branch block Dyssynchrony Animal research Cardiac resynchronization therapy
To maintain normal cardiac pump function, a near synchronous electrical activation sequence of both ventricles is imperative. This synchronous activation applies to multiple anatomic levels: within atria, between atria and ventricles, between ventricles, and especially within the left ventricle (LV). Right-sided pre-excitation, such as during left bundle branch block (LBBB) and right ventricular (RV) pacing, induces dyssynchrony, which instantly decreases cardiac pump function and is a risk factor for development of heart failure . Cardiac resynchronization therapy (CRT) attempts to treat dyssynchrony by simultaneous or sequential stimulation of both ventricles in patients with symptomatic heart failure, LV systolic dysfunction, and increased QRS complex duration. Even though large clinical trials clearly show the efficacy of CRT at the population level, in this heterogeneous group of patients, approximately one third does not show evidence of clinical or echocardiographic response after device implantation [2, 3, 4]. In addition, the range of response is highly variable, raising the question whether CRT is optimally performed in every patient or whether each patient can benefit equally from CRT. Therefore, a better understanding concerning the effects of dyssynchrony and resynchronization on cardiac pump function is required. The goal of the present article is to review how animal models of dyssynchrony can help clarify the pathophysiology of dyssynchrony and further improve the treatment of dyssynchrony by CRT.
Animal Models of Dyssynchrony
Over one century ago, Eppinger and Tothberger discovered large and specific changes in QRS morphology after making a small incision in the left or right surface of the interventricular septum in canine hearts . The first dyssynchronous animal model was established and was in fact a dyssynchrony model by a proximal lesion of the bundle branches. Since then, LBBB has been described in humans but also in monkeys and pigs [6, 7]. Investigating LBBB in other animals may apply less to the human situation, as there are inter-species differences in anatomy of the left bundle branch. For example, in hearts from ox and sheep, the bundles are significantly thicker and their branches extend much more towards the epicardium . In rabbit hearts, the left “bundle” is composed of groups of fine sheets covering the subendocardial tissue . Since the extent of electrical asynchrony in dogs is comparable to humans (where a doubling of QRS duration is seen), the canine heart is considered the most suitable animal model for investigating LBBB. In contrast, RV pacing and LBBB increases QRS duration by only 50% in pigs  and even less in goats (unpublished observations).
For obvious reasons, animal experiments have presented more detailed information than clinical studies, but they suffer from limitations such as the fact that most animal studies are performed in (initially) young and healthy animals and that various preparations have been used, which differ from the clinical and intact human situation. Because an animal model based on intraventricular incisions was not suitable to investigate the hemodynamic effects of LBBB, later research focused on dyssynchrony based on ventricular pacing. In 1925, Wiggers described that artificial stimulation of the canine left ventricle (1) slows down the rise of intraventricular pressure, (2) lengthens the isometric contraction phase, (3) lowers the maximal systolic pressure, and (4) increases the duration of systole . Even though it was clear that dyssynchrony has adverse effects on cardiac pump function, major interest in the pathophysiology of dyssynchrony developed only after these effects were revealed in large groups of patients who underwent permanent RV pacing . Similar to LBBB, RV pacing induces delays in transseptal and intraventricular conduction which explains why the hemodynamic effects of altered ventricular activation during RV pacing and LBBB are comparable. However, there are important differences between the two situations. RV apex pacing disturbs RV activation since pacing induces slow intramyocardial conduction instead of fast conduction through the Purkinje fibers. Secondly, the site of stimulation-induced breakthrough differs from the site of intrinsic breakthrough. Therefore, LV depolarization through the interventricular septum is also different from that during LBBB.
Myocardial contraction does not immediately follow depolarization, and the delay between local electrical activation and shortening, or electro-mechanical delay, was found to be approximately 30 ms in normal canine hearts . More advanced measurements (MRI tagging) at many sites in asynchronous ventricles showed that timing differences in shortening are larger than in electrical activation . This larger mechanical asynchrony is presumably explained completely by its definition: the onset of shortening. Recent studies in canine hearts indicate that when the onset of active force generation rather than the onset of shortening is used to define mechanical activation, electro-mechanical delay is equal throughout the asynchronous heart and directly reflects the timing of electrical activation . This discrepancy between onset of active force generation and onset of shortening is explained by the fact that early-activated regions can start to shorten immediately upon activation, because cavity pressure is low and all other muscle fibers are passive, while this is not valid for late activated regions (see also the short-axis echocardiography; Online Resource 2). The prolonged electro-mechanical delay in the later activated region could not be explained by increased excitation–contraction coupling time or increased pressure at the time of local depolarization. However, the higher rate of rise of LV pressure (dP/dt) that late activated regions have to oppose prolongs the interval when force generation is accelerated to a rate superior to load rise, resulting in delayed onset of shortening . Moreover, the septum contracts against a reduced load resulting in a faster than normal shortening during the isovolumic phase. This phenomenon can be used as an echocardiographic marker for dyssynchrony and is possibly able to predict response to CRT . Additionally, early septal contraction pre-stretches the left ventricular free wall and when this region starts to contract after its delayed onset of shortening will stretch the septum again . This combination of delayed onset of shortening, early septal shortening, and reciprocated stretching causes a less effective contraction and reduces the rate in rise of pressure. The early fiber shortening in early-activated regions and pronounced shortening in late activated regions found in canine dyssynchrony models was also found in LBBB patients [19, 22, 23]. Since LV dP/dt reflects LV function and contractility, the magnitude of mechanical dyssynchrony may vary over time in a given patient when there are changes in LV function .
The ventricular wall is capable of adapting to changes in workload by changing the extracellular matrix composition and by hypertrophy of cardiomyocytes. It is not entirely clear which mechanisms are responsible for initiating these changes, but neurohumoral and cardiac load have been ascribed to play an important role. Within the LV wall, an asynchronous electrical activation causes a redistribution of mechanical work, perfusion and oxygen demand [22, 24]. Ventricular pacing results in reductions in regional myocardial perfusion and oxygen consumption near the pacing site. Moreover, the larger mechanical load in late activated regions leads, in the long run, to increased wall thickness in regions opposing the site of pacing, while early-activated wall segments tend to become thinner [21, 22, 25]. The latter is even more the case in canine hearts, which were paced at the RV, while pressure overload was induced by aortic banding. In this model, no added hypertrophy was seen in the late-activated wall, but a clear inhibition of hypertrophy in the early-activated septum . The generally more pronounced hypertrophy in the pre-stretched regions indicates that the local mechanical load is an important stimulus in this remodeling process . On top of abnormal contraction, premature relaxation in early-activated regions and delayed contraction in others cause abnormal relaxation .
Myocardial Perfusion and Metabolism
To investigate regional myocardial blood flow, the microsphere deposition method can be used, the gold standard for regional blood flow measurements. After injection of radioactive or fluorescent microspheres, deposition is measured and thereby provides information on regional perfusion . During sinus rhythm, blood flow is homogeneous and equally distributed. However, in the dyssynchronous heart, early-activated regions consistently show a reduced myocardial blood flow, while higher flow is observed in late-activated regions [22, 28]. Closely related to myocardial blood flow is myocardial oxygen consumption (MVO2). Not surprisingly, MVO2 shows a similar distribution as myocardial blood flow, where early-activated regions show a reduction in MVO2 and a near normal oxygen consumption is observed in the latest activated regions . Oxygen extraction from the blood is not altered in the different regions and remains stable over a wide physiological range. Therefore, it is speculated that the local changes in workload, due to dyssynchronous contraction, changes the local oxygen demand and thereby local perfusion. In humans, dyssynchrony has usually a silent onset and is often first diagnosed when patients present themselves with other cardiovascular problems. Frequently non-invasive myocardial imaging is performed to diagnose perfusion defects due to coronary artery disease (CAD). However, septal perfusion defects are frequently found in patients with LBBB in the absence of any significant CAD [29, 30]. As argued above, the data from animal studies suggest that this effect in patients is probably due to reduced oxygen demand, caused by the underlying electrical substrate. An alternative hypothesis of the septal underperfusion in dyssynchronous hearts is that perfusion is hampered by the abnormal contraction, which augments intramyocardial pressure and shortens the diastolic period, where coronary perfusion occurs [31, 32, 33].
Changes in myocardial blood flow and workload are paralleled by changes in metabolism. In dogs with dyssynchronous hearts, glucose uptake in the septum is markedly reduced in a similar fashion as the redistribution in myocardial blood flow . In patients with dyssynchrony, a relative reduction of glucose uptake in the septum compared to the lateral wall is observed as assessed by fluorodeoxyglucose positron emission tomography imaging. However, the perceived reduction in glucose uptake in the septum may also be due to an increase in absolute glucose uptake in the lateral wall, caused by an increase in work load and higher energy demand in that wall .
Cardiac Resynchronization Therapy in Animal Models
The aforementioned findings give rise to the notion that dyssynchronous ventricular activation by LBBB on its own is sufficient for CRT to be efficient. The described animal models contain dyssynchronous activation either by ventricular pacing or by proximal ablation of the left bundle branch and, unlike CRT candidates, these models do not suffer from co-morbidities complicating their conduction defect. It is important to understand the effects of additional factors such as LV systolic dysfunction for better selection of CRT candidates and to improve response to treatment. In healthy canine hearts, isolated LBBB induces electrical and mechanical dyssynchrony that eventually will lead to loss of LV pump function and ventricular remodeling. In these hearts, CRT largely reversed global and regional function and structural abnormalities, indicating that LBBB as electrical substrate is sufficient for acute and long-term response to CRT . Recently, multiple clinical trials have indeed shown high CRT efficacy in heart failure patients who were not severely symptomatic (NYHA class I and II) [2, 40, 41, 42, 43].
Role of Infarction in CRT
While, based on these studies, inclusion criteria for CRT may be extended to patients without severe symptomatic heart failure, still a significant number of patients complying with the current guidelines do not respond to CRT. To this regard, most clinical studies show that the number of non-responders is highest in patients who suffer from ischemic cardiomyopathy (ICM). One possible mechanism is that there is insufficient viable tissue to allow an increase in contractility by CRT. Another possible mechanism lies in modification of the electrical substrate where the extent of resynchronization would be limited as a result of slow-conducting or non-conducting regions. This would mean that a good response to CRT in ICM patients not only requires clear conduction disease, but also the capability to properly resynchronize the heart. An important feature in this regard is the site of pacing as pacing in the vicinity of scar tissue is considered to compromise conduction.
Role of Dilation on Benefit of (Endocardial) CRT
Besides ventricular conduction delay and possibly myocardial infarction, many CRT candidates suffer from dilated cardiomyopathy. Even though dyssynchrony alone is sufficient for CRT to be successful, inducing heart failure in addition to electrical asynchrony can be essential to test certain hypotheses. For example, it was found that in canine hearts with isolated LBBB, endocardial LV pacing during CRT consistently improved systolic LV pump function, reduced electrical asynchrony, and decreased dispersion of repolarization, as compared to epicardial LV pacing at the same site . Three possible mechanisms explaining the more rapid electrical activation during endocardial CRT in this model were proposed: (1) shorter path length of conduction, (2) faster endocardial than epicardial conduction as well as (3) faster conduction from endocardium to epicardium than vice versa. While all three factors may contribute in the setting of LBBB in otherwise healthy canine hearts, ventricular dilatation and wall thinning would reduce the difference in conduction pathlength between endocardium and epicardium, potentially reducing the advantages of endocardial CRT in patients with dilated cardiomyopathy. Better understanding of the various factors determining the benefits of endocardial CRT in animal models with compromised hearts can also be used to propose explanations to ambivalent results reported from the few small clinical studies on endocardial CRT [46, 47, 48]. For this purpose, we performed a study to investigate the efficacy of endocardial CRT in canine LBBB hearts combined with dilated cardiomyopathy . The results were compared with endocardial CRT in dogs with acute LBBB and in dogs with chronic LBBB and infarction (model as described above). To obtain dilated cardiomyopathy, the apex of the right ventricle was paced at a rate of 220 beats per minute for 4 weeks, as described earlier by other groups [50, 51].
Pacing-induced tachycardia results in severe LV dilatation and decreases LV systolic function to levels similar to those found in heart failure patients. However, evaluating chronic effects of CRT in this model is only possible when tachycardia is maintained during resynchronization as the heart would recover independently from therapy. This model has been used to explore genetic alterations induced by dyssynchrony and the capability of CRT (at the same high rate) to restore these alterations . This model provided some interesting data, showing that even though heart rate remained high and hemodynamics hardly improved, electrical resynchronization and mechanical recoordination resulted in extensive cellular and molecular recovery [54, 55].
Canine models of dyssynchrony and associated left ventricular changes in hypertrophy, dilatation, EF, and dP/dt max
Animal models are of great importance in understanding the events and consequences of dyssynchrony and resynchronization. Depending on the hypothesis to be tested, multiple well-established and novel animal models of dyssynchrony exist. Detailed animal experiments demonstrate that ventricular dyssynchrony is a complex disease, which can and needs to be treated in a better way than it is often performed today.
This research was performed within the framework of CTMM, the Center for Translational Molecular Medicine (www.ctmm.nl), project COHFAR (grant 01C-203), and supported by the Dutch Heart Foundation.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
LV short-axis echocardiographic recording of a single-beat during normal conduction. (MPG 3172 kb)
Parasternal short-axis echocardiography recording of the left ventricle during left bundle branch block. (MPG 4202 kb)
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