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,Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio 44195
Submitted 14 April 2004 ; accepted in final form 8 July 2004
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ABSTRACT |
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 TOP ABSTRACT RESULTSDISCUSSIONGRANTSREFERENCES |
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heart failure; rate control; external cardiac work; oxygen consumption
CP consists of electrical stimulations applied to the heart after the effective refractory period of the each spontaneous ventricular activation. The somewhat similar concept of "paired stimulation" was proposed several decades ago as a therapy for heart failure (3, 8, 17). Paired stimulation paces the ventricles at a basic interval that is slightly less than the prevailing one during SR. Then, a second closely coupled electrical stimulus is applied. The second stimulus of each pair for both paired stimulation and CP is premature enough to result in no mechanical contraction. However, the second stimulus enhances contractility via postextrasystolic potentiation (6). Paired stimulation does not decrease the rate of mechanical contraction and necessitates artificial pacing of every beat, making it potentially harmful in the setting of high heart rate and normal ventricular conduction. In contrast, CP uses the intrinsic activation of the ventricles as the first of the paired ventricular "beats." In the case of CP, the paced beat (second of the paired activity) prevents the subsequent intrinsic activation. Thus the intrinsic activation of the ventricles occurs at half the prior rate. In both cases (paired stimulation and CP), the contractile state is enhanced (6). Paired stimulation resulted in the ventricular rate of mechanical contraction (VRMC) remaining the same, whereas CP resulted in VRMC decreasing to approximately half its original rate. Although paired stimulation (17) effectively increased systolic function, it increased markedly myocardial oxygen consumption (M
O2). A recent study (18) showed a new positive inotropic agent did not increase MO2 in heart failure because it resulted in a reflexly induced bradycardia. However, when this bradycardia was prevented, the MO2 increased. The purpose of this present study is to show that CP can reduce the rate of ventricular mechanical contractions and improve cardiac function during acute AF while not dramatically increasing MO2. We previously showed that CP dramatically increases the external work of the heart during AF (24). Thus, without a comparable increase in MO2, as occurs for external work during CP, the myocardial efficiency should improve.
The primary hypothesis of the present study is that CP improves cardiac function during acute AF (24) without a comparable increase of MO2. A secondary hypothesis of the study is that the presence of cardiac dysfunction (CD) enhances the effect of CP in AF.
METHODS
This investigation was approved by the Institutional Animal Research Committee at Cleveland Clinic Foundation, and it conforms to the Guide for the Care and Use of Laboratory Animals published by the National Institute of Health (NIH Pub. No. 85-23, Revised 1996).
Experimental protocol.
We used adult mongrel dogs (22–29 kg) in an experimental design that consisted of two phases. In phase 1 (n = 4 dogs), the aim was to establish and validate the method of external work per MO2 measurement under varying heart rhythm conditions. The experiments consisted of two stages: SR (stage 1) and AF (stage 2). Each stage lasted at least 10 min and was divided into two 5-min periods: before and after the application of CP. In each period, we collected data during the last 60 s. In phase 2 (n = 7 dogs), to study how concurrent CD alters the effects of CP on cardiac energetics during AF, we added two additional stages: CD and CD + AF (i.e., AF in the presence of CD). That is, we first reestablished SR. We then induced CD by administering 3–5% isoflurane in addition to the 
-chloralose anesthesia (stage 3). We chose this method of CD induction because we could titrate the extent of CD to a prescribed level of 
50% cardiac output that was found during SR (11). See Table 1 for the changes in hemodynamics resulting from this CD. After obtaining a stable but reduced cardiac output, we collected data before and during CP in the same manner as the first two stages. Finally, we induced AF during the acute CD and again obtained data before and during CP (stage 4).
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-chloralose (80 mg/kg iv). Supplemental anesthesia was given hourly. We started positive pressure ventilation. Normal arterial blood gas values and pH were maintained by appropriate adjustments throughout the experiment. We used micromanometer-tipped catheters (Millar; Houston, TX) to measure mean aortic pressure (mAoP) and left ventricular (LV) pressure (LVP). After a right thoracotomy, a third pressure catheter was inserted and advanced into a right pulmonary vein branch to measure left atrial pressure. We isolated the ascending aorta and placed a flow probe (Transonic Systems; Ithaca, NY) on the vessel. A quadrapolar catheter was placed in the right atrium via a femoral vein to induce AF by constant rapid pacing. A second quadrapolar catheter was placed in the right ventricular apex via the left jugular vein to sense the electrical activation of the ventricles and then to apply CP. We used a computer-controlled program (custom program by K. A. Mowrey) to apply CP via an analog-to-digital board (Microstar Lab; Bellevue, WA). The stimulation output was controlled from a Microsoft Excel program via a Microsoft Visual Basic interface with the analog-to-digital board. All the stimulation parameters and measurements of cardiac cycle lengths were controlled in real time. We determined the optimal parameters as described earlier (24). Because not all electrical activations of the left ventricle results in its mechanical contraction and this contraction does not always result in ejection of blood into the aorta, we measured the ventricular rate of electrical activations (VREA), VRMC, and ventricular rate of ejections (VREJ). We define the VREA as the rate of electrical activations (including both intrinsic activations and paced beats), VRMC as the rate of LV mechanical contractions that reach at least a developed pressure of 10 mmHg, and VREJ as the rate of measurable ejections from the left ventricle.
The azygos vein was isolated to insert our coronary sinus catheter. After the completion of this surgery, we heparinized the animal (500 U/kg). Via this vein, the tip of the coronary sinus catheter was inserted into the ostium of the coronary sinus, and the cuff at its distal end was inflated to divert all of the coronary sinus blood into the catheter. The proximal end of the catheter exited the azygos vein and was connected to silicone tubing that was used to return the blood to the animal via the right jugular vein. An in-line flow probe (Transonic 4N) was connected to this tubing. With this extracorporal system, we could continuously measure coronary blood flow and obtain periodic blood samples.
Data acquisition. All hemodynamic and electrogram measurements were continually monitored and periodically recorded at the times described above (Cardio Lab, GE Marquette Medical Systems). The above measurements were digitized and analyzed off-line with our custom data analysis software (K. A. Mowrey).
Measurement of stroke work. Single-beat stroke work was calculated as stroke work (in joules) = stroke volume (in ml, an integral of aortic flow rate) x (mean LVP during ejection in mmHg) x 1.33 x 104 (14). In four experiments, we validated this calculation with the calculation based on the area of individual pressure-volume loops obtained by a pressure-conductance catheter (Millar Instruments) (24).
Measurement of MO2.
From the coronary sinus-cervical venous circuit, we sampled the coronary sinus blood while simultaneously obtaining an arterial blood sample. From these two blood samples, we calculated the O2 extraction by the heart at each stage of the experiment. Next, we multiplied these O2 extractions by coronary blood flow rate to obtain MO2 rate (in ml/min) for each stage.
Because we did not observe dramatic increases in coronary blood flow during CP as reported during paired stimulation (17), we performed the following two tests. First, we would temporarily occlude the silicone tubing distal to the flow probe. This occlusion would build up pressure and caused increases in coronary blood flow following this occlusion that were much greater than any of the increases occurred during our experimental protocol. Thus the extracorporal circuit did not provide resistance that would limit a potential increase in coronary flow. Second, no marked increases in the extraction of oxygen or release of lactic acid was detected during AF, CD, or the application of CP, which would have indicated that the coronary vasculature could not increase its flow in a manner needed to match increased metabolic demands. Thus the coronary vasculature reserve was adequate in this present study.
Calculation of myocardial efficiency.
We defined external cardiac work (ECW) as the sum of stroke work over a 1-min period at the same time blood samples were taken to determine MO2. Stroke work from each ejection was calculated as the product of stroke volume times the mean LV ejection pressure. Prior work showed that hearts produce 20.2 J of energy for each milliliter of O2 consumed (1). Thus the myocardial efficiency of the heart was calculated as myocardial efficiency (%) = ECW (J/min)/[MO2 (ml/min) x 20.2] x 100.
Statistical analysis.
Data are present in our graphs as means ± SE. We used the paired t-test to separately examine the effects of CP on various ventricular function parameters (ventricular rate of mechanical contraction, mAoP, cardiac output, coronary blood flow, total stroke, or ECW per minute, MO2 per minute, and myocardial efficiency) during each of the four stages. In addition, we examined the overall effects of AF, CD, and CD + AF on the change in the above parameters when CP was applied in the last seven animals. In this later case, we used a two-factor repeated-measures ANOVA design to explore the effects of acute AF and CD: dependent variable (such as VRMC, mAoP, CO, etc.) = C + AF + CD + CD·AF + Di + Error where C is a constant, AF and CD denotes the presence or absence AF and CD, respectively, and Di (with i = 1... 7) denotes the individual dog effect. P values < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTRESULTSDISCUSSIONGRANTSREFERENCES |
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O2 did not increase (middle right) as much as ECW. Therefore, myocardial efficiency increased as a result of CP during all stages except SR (bottom right).
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O2 in response to CP. As a result, myocardial efficiency increased during CP (P = 0.007), with the increase more evident in the presence of CD (P = 0.007).
Effects of CP on electromechanical activation and ejection and the energetics of each contraction.
Table 2 is a summary of average VREA, VRMC, and VREJ as well as the MO2 and external work per beat. This application of CP results in approximately half of the intrinsic ventricular depolarizations that would have occurred. Thus the VREA remained virtually constant despite the additional paced stimulation from the CP. With these reductions in VRMC, VREJ equals the VRMC; that is, all contractions result in ejection of blood (100% ejections). In contrast, the percentage of ejections to ventricular contractions was 70% and 77% before the application of CP during AF and CD + AF. Thus the application of critically timed ventricular pacing (CP) reduced the VRMC to half its prior rate during AF and ensured that ejection of blood occurred after every contraction.
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Because changes in heart rate affect cardiac metabolism and there were wide ranges of the contractions and ejections rates in the four stages of this study before and after CP, we also measured MO2 and external work on a per beat basis (see lower portion of Table 2). Note that AF did not dramatically affect MO2 per contraction (0.45 vs. 0.41), whereas CP increased the MO2 by a factor of 2. The induction of CD resulted in a reduction of MO2 to approximately half its prior value. However, CP still increased MO2 by 2. During SR, the external work per beat doubled because the rate contraction decreased by half. In contrast, the external work per beat more than doubled when AF was present.
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DISCUSSION |
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TOPABSTRACTRESULTSDISCUSSIONGRANTSREFERENCES |
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O2 increased only moderately. As the ECW increased to a greater degree, the CP significantly increased myocardial efficiency during CD, both in the absence and presence of AF.
Cardiac function and O2 usage.
Paired stimulation was investigated as a potential therapy for heart failure because it directly increased myocardial contractility (3, 17). However, this therapy was abandoned because paired stimulation applied acutely also greatly increases MO2. This increase in MO2 could compromise an already ischemic heart (8, 17). Whereas the increase in MO2 in response to CP was moderate, the CP improved myocardial efficiency. We explain this important difference as follows: Heart rate, contractility, wall tension, and the extent of fiber shortening all influence MO2 (4, 17, 19). Because changes in MO2 correlate with changes in heart rate (2), the reduction of the rate of contraction by half with CP should decrease MO2 by half. In contrast, paired stimulation would result in no reduction in the rate of ventricular contraction. Although CP results in two electrical activations for each mechanical contraction, prior work has shown that electrical activation and repolarization of the heart uses less than 5% of the energy used each cardiac cycle (10). A positive increase in myocardial contractility (second factor) increases MO2 (19). Increases in LV wall tension normally elevate MO2 (third factor). However, because CP decreases both aortic diastolic pressure and LV end-systolic volume (24), changes in wall tension would have little effect increasing MO2 in our experiments. The doubling of stroke work via the doubling of stroke volume (fourth factor) (24) has less influence on MO2 than the other three factors (4). Finally, CP permits intrinsic activation of the ventricles, whereas paired stimulation results in an inefficient contraction due to pacing-induced ventricular dyssynchrony (22). In conclusion, the reduction in the rate of contraction appears to attenuate, to a large degree, the increases in MO2 that normally occur.
Concept of partitioning O2 usage. Because of the earlier work of Braunwald and colleagues (3, 5, 8, 10, 16), Suga and associates (20) established a concept of partitioning myocardial oxygen usage for contraction into nonrelated cellular metabolism, electromechanical coupling, contractility level, and generation of PV area (PVA), the last being a sum of external (stroke) work and potential energy.
Suga and co-workers (21) showed that paired pacing doubled contractility-dependent oxygen use per mechanical beat. In this work, contractile efficiency was defined as total contractile work (both potential energy and external work) per total energy expenditure (MO2). He and his colleagues demonstrated that paired stimulation resulted in an upward shift in the relationship between the total PVA (both potential and external work) and MO2. Because the inverse slope of this relationship was defined as contractile efficiency, which did not change, Suga concluded that PVA-independent oxygen consumption was augmented without affecting the contractile efficiency.
CP during rapid AF affects oxygen use through several opposing mechanisms. It eliminates the pressure-generating beats with no or little associated ejection, eliminating oxygen used for the development of potential energy of these beats. CP increases the stroke volume of ejecting beats. It reduces the rate of contraction, thus MO2. However, the postextrasystolic potentiation elicited by CP increases contractility-dependent oxygen use. Finally, CP had no effect on electromechanical coupling because the number of depolarization sequences remained constant.
In contrast to Suga and colleagues (20, 21) complex analysis of oxygen usage, our myocardial efficiency is the simple ratio of only external work [(stroke work/time)/total energy (MO2/time)]. Thus the "mechanically bradycardic" effect of CP increases the external work-to-potential energy area ratio by eliminating the aborted beats, thus improving efficiency of the ventricle as we defined it.
With the use of Suga and colleagues (20, 21) concepts of oxygen partitioning by the heart, a more recent study (25) showed that the contractile efficiency was maintained only if the negative chronotropic effect of 
-blockade was manifested. Therefore, the bradycardiac effect of -adrenergic blockade is important in preventing an increase in the energy expenditure for nonmechanical work. Once again, rate reduction is important in either maintaining efficiency or possibly enhancing it.
CP and O2 usage.
Only one previous study (9) assessed MO2 during CP somewhat similarly to ours. The study showed that CP increased MO2 by 66% and decreased myocardial efficiency by 50%. All patients had normal heart rates (average heart rate, 79 beats/min). CP induced bradycardia (heart rate, 44 beats/min) and decreased cardiac index by 34%. We found that during SR, our results with CP were similar to this clinical study. Our study differed from this clinical study in that we also assessed the effects of CP during tachycardia. Our experiments showed that CP was most effective as a therapy during tachycardia (acute AF, CD, and CD + AF). In conclusion, the slowing of the rate of contraction below normal levels causes a decrease in efficiency.
Clinical implications. The increasing prevalence of heart failure in patients and the detrimental effect of concurrent AF with concurrent heart failure provide a strong impetus for reexamination of this pacing therapy. We have shown that CP can increase LV pump function without adversely affecting myocardial efficiency in AF and in AF with concurrent LV dysfunction. Thus this therapy could potentially be applied in patients with ischemic heart disease, which accounts for many patients with HF. The improvement in ventricular function as the result of CP may outweigh the potential risk of the induction of ventricular tachycardia. To minimize the risk of this pacing therapy, such therapy could be given through a defibrillator and only during the times of tachycardia. Also, to reduce the risk of proarrhythmia, the coupled beat could be given with a paced output just slightly above the capture threshold. This pacing therapy could be applied via an existing right ventricular lead or a temporary lead, using either a new or modified pacemaker.
Pharmacological therapy, with all its disadvantages, could be avoided. Also by proper programming, CP should not cause excessive bradycardia. Finally, CP could have advantages over interruption of atrioventricular conduction by avoiding pacemaker dependence and by allowing intrinsic conduction of most ventricular beats.
Limitations.
The number of animals was small. Also, because this study was performed in an acute setting, we can only speculate about whether CP may become a viable therapy for chronic AF and/or heart failure. We are aware that our acute CD induced by excessive anesthesia is substantially different from chronic heart failure. Thus the compensatory responses of chronic heart failure with enlarged hearts and chronic AF may alter the heart's response to CP. However, the limited increases in MO2 in this study as opposed to paired stimulation (large increases in MO2) suggest that CP as pacing therapy should be reexamined during chronic AF and heart failure. The larger increases in external cardiac work compared with MO2 translate into an increase in myocardial efficiency during CP. However, if the MO2 increases moderately as the result of CP during chronic AF and HF, as we have observed in this acute study, some coronary flow reserve would need to be present in these patents to avoid myocardial ischemia and commitant-related issues.
The animals in this study have normal intraventricular conduction. However, this study does not answer how regional alterations in the conduction that sometimes occur in patients with heart failure would affect the extrasystolic interval of CP in various portions of the heart and thus the magnitude of regional changes in postextrasystolic potentiation. Further experiments are needed to determine how the coupling intervals of these premature beats affect the efficiency of these diseased hearts.
In conclusion, we clearly showed that CP improves myocardial efficiency in AF, CD, and CD + AF. With the evolution of pacemakers and internal defibrillators, this pacing algorithm may become a novel strategy for treating patients with AF and/or heart failure.
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GRANTS |
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TOPABSTRACTRESULTSDISCUSSIONGRANTSREFERENCES |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTRESULTSDISCUSSIONGRANTSREFERENCES |
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This article has been cited by other articles:
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  K. Mischke, M. Zarse, T. Schimpf, M. Baranowski, C. Knackstedt, J. Plisiene, and P. Schauerte Paired Ventricular Stimulation: An Approach for Hemodynamic Stabilization During Ventricular Tachycardia J. Am. Coll. Cardiol., June 6, 2006; 47(11): 2337 - 2339. [Full Text] [PDF]
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