Regional Deficits of Myocardial Blood Flow and Function in Left Ventricular Pacing–Induced Heart Failure
Background Pacing-induced congestive heart failure has become a preferred model for the study of the pathogenesis of dilated cardiomyopathy. However, little is known regarding regional myocardial blood flow and function during the development of heart failure in this model.
Methods and Results To determine whether regional differences in myocardial blood flow are associated with regional dysfunction in ventricular pacing–induced heart failure, regional myocardial blood flow (radioactive microspheres) and regional wall thickening (transthoracic echocardiography) were measured in pigs studied at weekly intervals during the progression of heart failure induced by rapid pacing from the lateral wall of the left ventricle (220±9 bpm for 26±4 days). Echocardiography and hemodynamic measurements with the pacemaker off showed progressive, severe global left ventricular dysfunction. During pacing over the 3- to 4-week period, a progressive decrease in systolic wall thickening in the lateral wall occurred compared with the interventricular septum (IVS; P=.001); at 21 to 28 days, the difference was 50% (lateral wall, 14±6%; IVS, 28±6%; P=.0001). A difference in subendocardial blood flow per beat between the left ventricular lateral wall (the site of stimulation) and the IVS was found immediately on the initiation of pacing (IVS, 0.009±0.002 mL · min−1 · g−1 · beat−1; lateral wall, 0.005±0.001 mL · min−1 · g−1 · beat−1; P=.001), a difference that was sustained during pacing throughout the study. Subendocardial blood flow per beat was normal in both regions with the pacemaker off throughout the study.
Conclusions These data indicate that regional myocardial ischemia is associated with the development of contractile dysfunction of the paced wall during prolonged rapid left ventricular pacing and that regional stunning contributes to persistent global left ventricular dysfunction when pacing is discontinued.
Chronic rapid ventricular pacing results in ventricular dilation, elevated ventricular diastolic pressures, and neurohormonal changes analogous to clinical dilated cardiomyopathy. Pacing-induced heart failure has become a popular model because of its relative simplicity, reproducibility, and similarities with many features of clinical dilated cardiomyopathy. Our group and others have shown that chronic rapid pacing results in left ventricular dilation with impaired systolic function.1 2 3 4 5 6 7 8
Many factors may contribute to the pathogenesis of heart failure in this model, including ischemia, abnormalities of calcium homeostasis,9 and reduced sarcoplasmic reticulum Ca2+-ATPase activity,10 but the mechanism remains unclear. The model is associated with minor degrees of subendocardial injury and fibrosis, unchanged left ventricular mass, and decreased collagen content.6 11 12 Preliminary echocardiographic images from our laboratory indicated that sustained ventricular pacing induces differences in regional left ventricular contraction analogous to regional functional abnormalities seen in clinical ischemic heart disease. In the present study, we sought to determine the acute and chronic effects of rapid ventricular pacing on regional myocardial blood flow and function.
Several recent studies examined myocardial blood flow in pacing-induced heart failure13 14 15 and found reduced myocardial blood flow after the onset of heart failure. However, the extent to which reduced myocardial blood flow caused heart failure rather than resulted from chamber dilation, wall thinning, and increased wall tension was not established. No prior studies have reported regional left ventricular blood flow and function sequentially in this model during sustained ventricular pacing. Therefore, we conducted the present study to determine whether regional differences in left ventricular systolic function occur and are associated with corresponding differences in myocardial blood flow.
Animals and Surgical Procedure
Nine Yorkshire pigs (Sus scrofa) weighing 40±6 kg were anesthetized with ketamine (50 mg/kg IM) and atropine sulfate (0.1 mg/kg IM) followed by sodium amytal (100 mg/kg IV). After endotracheal intubation, halothane (0.5% to 1.5%) was delivered by a pressure-cycled ventilator throughout the procedure. At left thoracotomy, catheters were placed in the aorta, pulmonary artery, and left atrium. A Konigsberg micromanometer was placed into the left ventricular apex, and an epicardial unipolar lead was placed 1.0 cm below the atrioventricular groove in the lateral wall of the left ventricle. The power generator (Spectrax 5985; Medtronic, Inc) was inserted into a subcutaneous pocket in the abdomen. Four animals were instrumented with a flow probe (Transonic, Inc) around the main pulmonary artery. The pericardium was loosely approximated and the chest closed. Seven to 10 days after thoracotomy, baseline measures of hemodynamics, left ventricular function, and myocardial blood flow were made. Ventricular pacing then was initiated (220±9 bpm for 26±4 days). The stimulus amplitude was 2.5 V, the pulse duration 0.5 ms. Nine additional pigs (40±7 kg) were used as controls; five underwent thoracotomy and instrumentation without pacing and were killed 30±7 days after initial thoracotomy. Data regarding right and left ventricular mass were similar in the control animals whether they had undergone thoracotomy or not, so their data were pooled into a single control group.
Hemodynamic data were obtained from conscious, unsedated animals after the pacemaker had been inactivated for at least 1 hour and animals were in a basal state. All data were obtained in each animal at 7-day intervals. Pressures were obtained from the left atrium, pulmonary artery, and aorta. Left ventricular dP/dt was obtained from the high-fidelity left ventricular pressure. Pulmonary artery flow was recorded. Aortic and pulmonary blood samples were obtained for calculation of arteriovenous oxygen content difference.
Two-dimensional and M-mode images were obtained with a Hewlett Packard Sonos 1500 imaging system. Images were obtained from a right parasternal approach at the mid–papillary muscle level and recorded on VHS tape. Measurements were made according to criteria of the American Society of Echocardiography.16 Because of the midline orientation of the porcine interventricular septum (IVS) and use of the right parasternal view, short-axis M-mode measures were made through the IVS and the anatomic lateral wall. All parameters, including end-diastolic dimension (EDD), end-systolic dimension (ESD), and wall thickness, were measured on at least five random end-expiratory beats and averaged. End-diastolic dimension was obtained at the onset of the QRS complex. End-systolic dimension was taken at the instant of maximum lateral position of the IVS or at the end of the T wave. Left ventricular systolic function was assessed by use of fractional shortening, FS=[(EDD−ESD)/EDD]×100. Percent wall thickening (%WTh) was calculated as %WTh=[(ESWTh−EDWTh)/EDWTh]×100. To demonstrate reproducibility of echocardiographic measurements, animals were imaged on 2 consecutive days before the pacing protocol was initiated. The data from the separate determinations were highly reproducible (fractional shortening, R2=.94, P=.006; lateral wall thickening, R2=.90, P=.005). All of these measurements were obtained with pacemakers inactivated.
Myocardial Blood Flow
Myocardial blood flow was determined by the radioactive microsphere technique as described in detail in previous reports.17 18 Transmural samples from the left ventricular lateral wall and IVS were divided into endocardial, midwall, and epicardial thirds, and blood flow to each third and transmural flow were determined. Transmural sections were taken from regions in which echocardiographic measures had been made so that blood flow and functional measurements corresponded within each bed. Microspheres were injected in the control state (unpaced), at the initiation of ventricular pacing (225 bpm), and then at 7-day intervals during ventricular pacing at 225 bpm; microspheres were also injected with the pacemakers inactivated at 14 days (n=4) and 21 to 28 days (n=3). By dividing myocardial blood flow by the heart rate (recorded during microsphere injection), we calculated the myocardial blood flow per beat.19 Mean left atrial and mean arterial pressures were recorded during microsphere injection so that an estimate of coronary vascular resistance could be calculated: coronary vascular resistance index (mm Hg ·mL−1 · min−1 · g−1)=mean arterial pressure minus mean left atrial pressure divided by transmural coronary blood flow.
Systolic Wall Stress
Circumferential systolic wall stress could not be determined because we could not obtain a suitable view to estimate the long axis of the left ventricle. Therefore, we calculated meridional end-systolic wall stress20 using the equation meridional end-systolic wall stress (dynes)=(0.334×P×D)÷[h(1−h/D)], where P is left ventricular end-systolic pressure in dyne, D is left ventricular end-systolic diameter in cm, and h is end-systolic wall thickness. Meridional end-systolic wall stress was calculated for both lateral wall and IVS before the initiation of pacing and subsequently at weekly intervals (pacemaker off).
After 26±2 days of pacing, animals were anesthetized and intubated, and midline sternotomies were made. The still-beating hearts were submerged in saline (4°C), the coronary arteries were rapidly perfused with saline (4°C), the right ventricle and left ventricle (including IVS) were weighed, and transmural samples from each region were rapidly frozen in liquid nitrogen and stored at a temperature of −70°C.
ATP and ADP were measured in transmural samples of the IVS and lateral wall in four animals with heart failure (paced 28 days) and four control animals. The samples from the animals with heart failure were obtained with the pacemakers off (60 minutes) on the day the animals were killed. Samples were obtained identically in all animals. ATP and ADP were measured on a Waters high-performance liquid chromatograph as previously described.21
Data are expressed as mean±SD. Specific measurements obtained in the control (prepaced) state and at 1-week intervals during pacing were compared by repeated measures ANOVA (Crunch4, Crunch Software Corp). In some comparisons (lateral wall versus IVS, for example), two-way ANOVA was used. Post hoc comparisons were performed with the Tukey method. Nine animals survived 21 days of pacing; six of these survived 28 days of pacing. Data from animals surviving 28 days were statistically indistinguishable from those who survived only 21 days. ANOVA was conducted, therefore, on nine animals at four time points: control (prepacing), 7 days, 14 days, and 21 to 28 days. The null hypothesis was rejected when P<.05 (two-tailed).
Rapid ventricular pacing resulted in changes in hemodynamics that were significant after 7 to 14 days of pacing. At 7 days, animals had increased mean left atrial and pulmonary arterial pressures. These pressures became increasingly abnormal with additional weeks of pacing (Table 1⇓). Signs of circulatory congestion (tachypnea, ascites, and tachycardia) were evident by 14 to 21 days. Pulmonary arterial flow (cardiac output) had decreased by 21 days of pacing (control, 3.3±0.1 L/min; 21 days, 1.9±0.4 L/min; P<.05).
Global Left Ventricular Function
Left ventricular function was assessed by echocardiography and hemodynamic variables after pacemakers had been inactivated. Fractional shortening was progressively reduced with duration of pacing (P=.0001; Table 1⇑), reaching its lowest value at 21 to 28 days (control, 39±3%; 21 to 28 days, 13±4%; P<.0002). Left ventricular end-diastolic dimension progressively increased during pacing (P<.0001; Table 1⇑), reaching its maximal value at 21 to 28 days (control, 3.9±0.4 cm; 21 to 28 days, 5.8±0.6 cm; P=.0002).
Left ventricular peak positive dP/dt also decreased throughout the study (P=.0001; Table 1⇑). The progressive fall in peak dP/dt was accompanied by increasing left ventricular end-diastolic pressure, documenting decreased left ventricular contractility, since increased preload normally augments left ventricular peak dP/dt.22
Left Ventricular Regional Function
With the pacemaker inactivated, regional left ventricular function was assessed by measurement of percent wall thickening of the left ventricular lateral wall and IVS. Ventricular pacing from the lateral wall caused significant deterioration in function of the lateral wall compared with the IVS (P=.001; Fig 1⇓ and Table 2⇓). This difference was significant at 7 days and increased further at 21 to 28 days as lateral wall function deteriorated. The IVS showed an insignificant decrease in wall thickening over the course of the study. End-diastolic wall thickness showed progressive thinning during the study that was more severe in the lateral wall (Table 2⇓).
Left Ventricular Regional Blood Flow
Subendocardial blood flow per minute increased more in the IVS than in the lateral wall when pacing was initiated (Fig 2⇑ and Table 3⇓). This difference in regional blood flow during pacing persisted for the duration of the study, and the pattern of change in blood flow was different between the two regions (P=.006). The pattern of change in blood flow per minute between the two regions during pacing was consistent whether measured in endocardial (P=.006), midwall (P=.002), epicardial (P=.016), or transmural (P=.003) sections (Table 3⇓). In contrast, when the pacemaker was inactivated, subendocardial blood flow showed no regional differences whether measured in the control state, at 14 days, or at 21 to 28 days (Fig 2⇓ and Table 3⇓).
Endocardial-to-epicardial blood flow ratios did not change significantly as heart failure progressed (P=.058). However, with the initiation of pacing, the endocardial-to-epicardial ratio was substantially lower in the lateral wall than in the IVS (IVS, 1.32±0.23; lateral wall, 0.77±0.10; P=.0002; Table 3⇑). Ratios in both regions were >1.0 throughout the rest of the study.
Endocardial blood flow per beat (Fig 2⇑ and Table 4⇓) was similar in both regions before the initiation of pacing (IVS, 0.013±0.003 mL · min−1 · g−1 · beat−1; lateral wall, 0.012±0.004 mL · min−1 · g−1 · beat−1; P=NS). On initiation of ventricular pacing (225 bpm), there was a regional deficit in endocardial blood flow per beat in the lateral wall but not in the IVS (IVS, 0.009±0.002 mL · min−1 · g−1· beat−1; lateral wall, 0.005±0.001 mL · min−1 · g−1· beat−1; P=.001). At 14 days and 21 to 28 days, endocardial flow per beat was less in the lateral wall than in the IVS during pacing (Fig 2⇑ and Table 4⇓). These data indicate that myocardial hypoperfusion in the lateral wall began with the onset of pacing, and this relative ischemia persisted. However, endocardial blood flows per beat remained normal in both regions with the pacemaker off (Fig 2⇑ and Table 4⇓).
Blood flow in both regions tended to increase during the final week of pacing (Fig 2⇑ and Table 3⇑). This pattern was associated with a progressive fall in the coronary vascular resistance index (Fig 3⇓), suggesting that alterations in coronary vascular structure and function may accompany left ventricular remodeling as heart failure progresses. The coronary vascular resistance index was significantly greater in the lateral wall than in the IVS at the initiation of pacing, and the pattern of change in coronary vascular resistance was different between the two regions (P=.0012) (Fig 3⇓). These findings may indicate an effect of altered electrical activation on myocardial perfusion.
Left Ventricular End-Systolic Wall Stress
There was a significant increase in estimated meridional end-systolic wall stress with respect to duration of pacing (P<.0001), but the pattern of change in wall stress was similar for the lateral wall and IVS (P=.33), and post hoc testing failed to show any regional differences in systolic wall stress at any specific time point (Fig 3⇑). The increase in end-systolic wall stress was roughly threefold in the lateral wall (control, 168±40×103 dynes; 28 days, 412±143×103 dynes; P=.0001) and in the IVS (control, 159±35×103 dynes; 28 days, 480±225×103 dynes; P=.0001).
At necropsy, animals with heart failure had ascites (mean amount, 1809 mL; range, 300 to 3500 mL) and dilated, thin-walled hearts, with all four chambers appearing grossly enlarged. Ratios of ventricular weight to body weight suggested hypertrophy of the right ventricle only, confirming data from a previous study using this model.6 Compared with weight-matched control animals, there was no change in left ventricular mass associated with heart failure (control, 112±10 g; heart failure, 114±17 g); ratios of left ventricular weight to body weight were also similar in both groups (control, 2.8±0.3 g/kg; heart failure, 2.9±0.3 g/kg). In contrast, heart failure was associated with increased right ventricular weight (control, 38±3 g; heart failure, 52±11 g; P=.003) and ratios of right ventricular weight to body weight (control, 0.9±0.1 g/kg; heart failure, 1.3±0.3 g/kg; P<.003).
Paced animals gained 4 kg during the course of the study, an amount accounted for by ascites accumulation. If the initial body weight is used to calculate the ratio of left ventricular weight to body weight, the ratio still is not significantly higher than that from weight-matched control animals. These data confirm that there was no substantive increase in left ventricular mass during the course of the study.
Control animals showed normal ATP/ADP ratios, similar to those reported in pig heart collected by drill biopsies followed by immediate submersion in liquid nitrogen,23 documenting that the sampling techniques used were suitable. Animals with heart failure showed a marked reduction in ATP/ADP ratio in samples taken from the IVS (control, 14.8±1.1; heart failure, 2.4±0.3; P<.0001, n=4 both groups) and from the lateral wall (control, 14.3±4.0; heart failure, 2.4±0.9; P=.0012, n=4 both groups).
The most important finding of this study is that regional variations in myocardial blood flow, an immediate consequence of rapid ventricular pacing, may play a role in the pathogenesis of regional and global dysfunction in pacing-induced heart failure. During pacing, we found a difference in myocardial blood flow per minute between the left ventricular lateral wall (adjacent to the site of stimulation) and the IVS. Reduced blood flow was present in the lateral wall immediately on the initiation of pacing and remained for 21 to 28 days. The left ventricular lateral wall, receiving less blood flow than the IVS during pacing, showed progressive reduction in wall thickening (pacer off) during 21 to 28 days of pacing. In contrast, the IVS, receiving greater blood flow during pacing, maintained relatively normal wall thickening through 21 to 28 days of pacing. To the best of our knowledge, this is the first study that has examined regional myocardial blood flow and function sequentially during the development of ventricular pacing–induced heart failure. Wilson et al24 found similar changes in regional wall thickening in dogs after 3 weeks of rapid pacing from the left ventricular apex, but their study did not explore the pathogenesis for regional dysfunction. Their global measurements of left ventricular lactate production and oxygen extraction, reported to be unchanged, may have been insensitive to regional changes in metabolism.
Because myocardial blood flow per minute does not readily permit assessment of relative myocardial ischemia, we also expressed coronary flow as endocardial blood flow per beat. The physiological basis for such an analysis lies in previous experiments showing that regional subendocardial blood flow per minute (rather than outer wall or transmural flow) is the primary determinant of regional myocardial contraction under conditions of progressive coronary artery stenosis25 and that increases in heart rate shift this flow-function relation downward, with lower regional function at any level of subendocardial blood flow.19 However, if the flow-function relation is plotted as regional function versus endocardial blood flow per beat, to correct for heart rate effects, there is a single relation at different heart rates, indicating that endocardial blood flow per beat primarily determines the level of wall function when coronary blood flow is reduced.19 26 With the initiation of pacing, there was a >50% reduction in endocardial blood flow per beat in the lateral wall compared with the IVS (P<.001; Table 4⇑). In prior studies in the conscious pig, we have documented that a 50% reduction in endocardial blood flow caused a 50% reduction of regional function and was associated with a subendocardial flow per beat similar to that observed in the lateral wall in the present studies (Table 4⇑; Reference 27). The reduction in blood flow in the lateral wall during pacing persisted throughout the study. These data provide evidence for myocardial ischemia in the lateral wall on initiation of ventricular pacing. In contrast, IVS function and endocardial flow per beat remained relatively normal. With the pacemaker off, subendocardial blood flow per beat remained normal in both regions throughout the study, while regional dysfunction persisted in the lateral wall, consistent with the occurrence of myocardial stunning in that region.
Spinale at al15 measured myocardial blood flow before and after 3 weeks of rapid atrial pacing (240 bpm) in pigs. Initial resting myocardial blood flow was elevated (2.1 mL · min−1 · g−1), and during acute atrial pacing (240 bpm), myocardial blood flow increased further (3.1 mL · min−1 · g−1). Their data indicate that myocardial blood flow per beat remained normal during initial atrial pacing (0.012 mL · min−1 · g−1 · beat−1). However, after heart failure had developed, resting myocardial blood flow per beat was reduced (0.008 mL · min−1 · g−1 · beat−1) and increased minimally with atrial pacing. After heart failure, resting heart rate was higher, and myocardial blood flow per beat decreased 13%. After heart failure, atrial pacing was associated with a 61% decrease in myocardial blood flow per beat (versus before heart failure). These data indicate the presence of global ischemia during rapid atrial pacing. Our measurements of coronary blood flow were made during and after discontinuation of chronic ventricular pacing, rather than acute atrial pacing, as in the study by Spinale et al.15 Spinale et al also reported diminished coronary vasodilator reserve after pacing-induced heart failure, which may have impaired the responses to acute pacing. Komamura et al13 measured myocardial blood flow in the free wall of the left ventricle within 3 weeks of right ventricular pacing in dogs. With the pacemaker inactivated, transmural flow was reduced. These studies did not address whether abnormal responses of myocardial blood flow in response to pacing precede ventricular dysfunction or result from increased wall tension after left ventricular chamber dilation and wall thinning. Shannon et al,14 using a canine model of right ventricular pacing–induced heart failure, found that abnormalities in endocardial blood flow were rectified by reduction in left ventricular end-diastolic pressure, suggesting that myocardial blood flow abnormalities associated with this model may reflect altered hemodynamics, rather than changes in the coronary circulation itself.
Several observations may help to explain the apparent disparities in data regarding myocardial blood flow in pacing-induced heart failure. First, the site of pacemaker activation within the heart is an important determinant of myocardial blood flow.28 29 30 Since previous studies have used right ventricular,14 atrial,15 or left ventricular pacing,6 24 this consideration is germane. Second, an endocardial blood flow of 1 to 2 mL · min−1 · g−1 may be inadequate to meet the metabolic needs of a dilated, thin-walled, rapidly contracting heart. Hence, the reported variations in blood flow in various studies may represent ischemia, which might be evident only if assessed as endocardial blood flow per beat.
We found that deficits in myocardial blood flow in the left ventricular lateral wall relative to the IVS were immediate on initiation of pacing; functional deficits in this wall became apparent after 7 days of pacing, before significant chamber enlargement. The relative reduction in myocardial blood flow precedes ventricular remodeling and, therefore, may contribute to the pathogenesis of heart failure in this model.
The cause of regional differences in subendocardial blood flow is not entirely clear. Flow may be impeded by the dyssynergic contraction, particularly near the site of initial activation.29 30 Indeed, dyssynergic contraction due to ventricular pacing decreases myocardial blood flow in the earliest activated regions and in the subendocardium, where impedance to flow is greatest.28 29 31 Prinzen et al28 and Delhaas et al29 produced asynchronous activation from different ventricular sites and found that myocardial blood flow and fiber strain were highest in late-activated regions, whereas with atrial pacing, distribution of blood flow and strain was uniform. If dysfunction were due to ischemia, greater dysfunction might be anticipated in the subendocardium than the subepicardium because of the limited coronary vasodilator reserve of the subendocardium. Indeed, Waldman and Covell32 found progressive deterioration in function from subepicardium to subendocardium during acute ventricular pacing. These data and our own suggest that abnormal activation impairs myocardial blood flow most significantly in the region paced.
Regional differences in myocardial oxygen demand also could influence myocardial blood flow. If regional loading conditions were different in the IVS versus the lateral wall, function and thus myocardial oxygen consumption might be different. However, a regional difference in myocardial metabolic demand due to abnormal activation does not explain the persistent functional deficit in the lateral wall during normal activation (pacemaker off), when regional differences in myocardial oxygen demand should not be present. However, if blood flow to the lateral wall during rapid ventricular asynchronous contraction were insufficient to support metabolic requirements, regional ventricular function might eventually become depressed whether paced or not. This is what we found in the present study. The persistence of regional dysfunction during normal activation (pacemaker off), despite return of normal myocardial blood flow, is consistent with a stunning effect.33 Other studies have shown that systolic ventricular function returns to normal in pacing-induced heart failure 3 weeks after pacing is discontinued,34 indicating reversible dysfunction.
Since global left ventricular function was depressed, the significance of the relatively well-preserved septal function and blood flow during pacing is not clear. It may represent reciprocal regional hyperfunction in response to lateral dysfunction as seen in regional ischemia35 and may not be representative of the remainder of the ventricle. Whether the remainder of the ventricle becomes depressed by nonischemic or ischemic mechanisms, we postulate that sustained ischemia of the lateral wall has a significant effect on global function during and after pacing.
Other reports have suggested that pacing-induced heart failure is associated with ischemia. For example, O'Brien et al10 reported decreased myocardial energy reserves (ATP, phosphocreatine, and myocardial creatine) after rapid ventricular pacing. Histological analyses of myocardium from animals after sustained rapid atrial pacing indicate decreased collagen content with minimal subendocardial fibrosis.12 Decreased myocardial collagen content has been observed in cardiac remodeling due to ischemic heart disease.36 Therefore, many features of this model suggest that a relative blood flow deficit during continuous pacing may contribute to dysfunction. However, despite preserved function and blood flow compared with the lateral wall, the IVS undergoes significant wall thinning during the 21 to 28 days of pacing. We cannot exclude the possibility that relative ischemia, with inadequate blood flow for the level of heart rate increase, may contribute to wall thinning of the IVS. However, factors other than relative ischemia may also be operative in the pathogenesis for remodeling and chamber dilation in this model.
This study has some limitations. A major emphasis of our laboratory is in obtaining data from conscious, unsedated animals. A limitation of this approach is that direct measures of myocardial metabolic changes such as regional lactate production cannot be obtained. So far, these data have been obtained only from anesthetized animals with indwelling catheters in the coronary sinus or great cardiac vein in which radioactive substrates were used.37 To circumvent these problems, we have relied on measures of regional myocardial flow and function to determine whether differences in regional blood flow are relevant, since other studies have shown close coupling between decreasing myocardial blood flow and regional function.19 25 26 We recognize that such evidence remains indirect. LeGrice et al,38 using the same porcine model with pacing from the lateral wall, found that the regional dysfunction observed in the lateral wall (pacer off) was found predominantly in the endocardial portion of the wall, providing further support to an ischemic basis for the dysfunction. The marked reduction in ATP/ADP ratios found in myocardial samples in the present study confirms an imbalance between myocardial oxygen supply and demand.
The pathogenesis of pacing-induced heart failure may not be directly relevant to the pathogenesis of most causes for clinical dilated cardiomyopathy. However, these data are relevant for future studies using the ventricular pacing–induced model of heart failure. For example, since this model is associated with relative underperfusion of the left ventricular lateral wall, sustained rapid left ventricular pacing may be a better model of ischemic than idiopathic dilated cardiomyopathy, particularly in terms of alterations in the lateral wall. Moreover, since wall thickening is not clearly abnormal in the IVS, the model provides two regions of myocardium susceptible to a similar hormonal milieu but with distinct differences in blood flow and function. It is interesting to speculate that alterations in adrenergic signaling in this model may also have regional specificity, implying that regional rather than systemic factors may be critical in the molecular pathogenesis of heart failure.
In summary, sustained rapid ventricular pacing results in heart failure with a dilated, poorly contractile left ventricle. Rapid ventricular pacing from the lateral wall of the left ventricle results in reduction of blood flow to the lateral wall relative to the IVS, with a corresponding deficit in regional function that persists even when the pacemaker is inactivated and regional blood flow differences have returned to normal. The pathogenesis of heart failure due to sustained rapid ventricular pacing remains to be firmly established. However, data from this study suggest that myocardial ischemia plays an important role.
Dr Helmer was supported by an Associate Investigator Award from the Department of Veterans Affairs. This work was supported by Merit Awards from the Department of Veterans Affairs (Drs Shabetai and Hammond), NIH Research Career Development Award HL-02812-01 (Dr Hammond), and Specialized Center of Research Grant HL-537730-01 (Drs Ross and Hammond).
- Received March 27, 1995.
- Revision received June 3, 1996.
- Accepted June 5, 1996.
- Copyright © 1996 by American Heart Association
Armstrong PW, Stopps SE, Ford SE, de Bold AJ. Rapid ventricular pacing in the dog: pathophysiologic studies of heart failure. Circulation. 1986;74:1075-1084.
Calderone AM, Bouvier K, Li C, Juneau C, de Champlain J, Rouleau JL. Dysfunction of the β- and α-adrenergic systems in a canine model of congestive heart failure. Circ Res. 1991;69:332-343.
Kiuchi K, Shannon RP, Komamura K, Cohen DJ, Bianchi C, Homcy CJ, Vatner SF, Vatner DE. Myocardial β-adrenergic receptor function during the development of pacing-induced heart failure. J Clin Invest. 1993;91:907-914.
Marzo KP, Frey MJ, Wilson JR, Liang BT, Manning DR, Lanoce V, Molinoff PB. β-Adrenergic receptor–G protein–adenylate cyclase complex in experimental canine congestive heart failure produced by rapid ventricular pacing. Circ Res. 1991;69:1546-1556.
Roth DA, Urasawa K, Helmer GA, Hammond HK. Downregulation of cardiac guanosine 5′-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure. J Clin Invest. 1993;91:939-949.
Spinale FG, Zellner JL, Tomita M, Crawford FA, Zile MR. Relation between ventricular and myocyte remodeling with the development and regression of supraventricular tachycardia–induced cardiomyopathy. Circ Res. 1991;69:1058-1067.
Whipple GH, Sheffield LT, Woodman EG, Theophilis C, Friedman S. Reversible congestive heart failure due to chronic stimulation of the normal heart. Proc N Engl Cardiovasc Soc. 1962;20:39-40.
Perreault CL, Shannon RP, Komamura K, Vatner SF, Morgan JP. Abnormalities in intracellular calcium regulation and contractile function in myocardium from dogs with pacing-induced heart failure. J Clin Invest. 1992;89:932-938.
Spinale FG, Hendrick DA, Crawford FA, Smith AC, Hamada Y, Carabello BA. Chronic supraventricular tachycardia causes ventricular dysfunction and subendocardial injury in swine. Am J Physiol. 1990;259:H218-H229.
Spinale FG, Tomita M, Zellner JL, Cook JC, Crawford FA, Zile MR. Collagen remodeling and changes in LV function during development and recovery from supraventricular tachycardia. Am J Physiol. 1991;261:H308-H318.
Komamura K, Shannon RP, Pasipoularides A, Ihara T, Lader AS, Patrick TA, Bishop SP, Vatner SF. Alterations in left ventricular diastolic function in conscious dogs with pacing-induced heart failure. J Clin Invest. 1992;89:1825-1838.
Shannon RP, Komamura K, Shen Y-T, Bishop SP, Vatner SF. Impaired regional subendocardial coronary flow reserve in conscious dogs with pacing-induced heart failure. Am J Physiol. 1993;264:H801-H809.
Spinale FG, Zellner JL, Tomita M, Temple GE, Crawford FA, Zile MR. Tachycardia-induced cardiomyopathy: effects on blood flow and capillary structure. Am J Physiol. 1991;261:H140-H148.
Sahn DJ, DeMaria AN, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation. 1978;58:1072-1083.
Roth DM, Maruoka Y, Rogers J, White FC, Longhurst JC, Bloor CM. Development of coronary collateral circulation in left circumflex ameroid-occluded swine myocardium. Am J Physiol. 1987;253:H1279-H1288.
Roth DM, White FC, Nichols ML, Dobbs SL, Longhurst JC, Bloor CM. Effect of long-term exercise on regional myocardial function and coronary collateral development after gradual coronary occlusion in pigs. Circulation. 1990;82:1778-1789.
Indolfi C, Guth BD, Miura T, Miyazaki S, Schultz R, Ross J. Mechanisms of improved ischemic regional dysfunction by bradycardia: studies on UL-FS 49 in swine. Circulation. 1989;80:933-993.
Riechek N, Wilson J, Sutton M St J, Plappert TA, Goldberg S, Hirshfield JW. Noninvasive determination of left ventricular end-systolic wall stress: validation of the method and initial application. Circulation. 1982;65:99-108.
Pilz RB, Willis RC, Boss GR. The influence of ribose 5-phosphate availability on purine synthesis of cultured human lymphoblasts and mitogen-stimulated lymphocytes. J Biol Chem. 1984;259:2927-2935.
White FC, Boss G. Inotropic interventions during myocardial stunning in the pig. J Cardiovasc Pathol. 1990;3:225-236.
Wilson JR, Douglas P, Hickey WF, Lanoce V, Fararo N, Muhammad A, Reichek N. Experimental congestive heart failure produced by rapid ventricular pacing in the dog: cardiac effects. Circulation. 1987;75:857-867.
Gallagher KP, Matsuzaki M, Koziol JA, Kemper WS, Ross J Jr. Regional myocardial perfusion and wall thickening during ischemia in conscious dogs. Am J Physiol. 1984;16:H727-H738.
Ross J. Myocardial perfusion-contraction matching: implications for coronary heart disease and hibernation. Circulation. 1991;83:1076-1083.
Prinzen FW, Cornelis HA, Arts T, Allessie MA, Reneman RS. Redistribution of myocardial fiber strain and blood flow by asynchronous activation. Am J Physiol. 1990;259:H300-H308.
Saito D, Takeda K, Hyodo T, Abe Y, Tani H, Nagahana H, Uchida T, Haraoka S, Nagashima H. Effect of pacemaker sites on contractile forces of the local myocardium and blood flow in the major branches of the left coronary artery in anesthetized open-chest dogs. Jpn Circ J. 1984;48:331-335.
Downey JM, Kirk ES. Inhibition of coronary blood flow by a vascular waterfall mechanism. Circ Res. 1975;36:753-760.
Waldman L, Covell JW. Effects of ventricular pacing on finite deformation in canine left ventricles. Am J Physiol. 1987;252:H1023-H1030.
Matsuzaki M, Gallagher KP, Kemper WS, White FC, Ross J. Sustained regional dysfunction produced by prolonged coronary stenosis: gradual recovery after reperfusion. Circulation. 1983;68:170-182.
Tomita M, Spinale FG, Crawford FA, Zile MR. Changes in left ventricular volume, mass, and function during the development and regression of supraventricular tachycardia-induced cardiomyopathy: disparity between recovery of systolic versus diastolic function. Circulation. 1991;83:635-644.
Kumada T, Karliner JS, Pouleur H, Gallagher K, Shirato K, Ross J Jr. Effects of coronary occlusion on early ventricular diastolic events in conscious dogs. Am J Physiol. 1979;237:H542-H549.
Guth BD, Wisneski JA, Neese RA, White FC, Heusch G, Mazer CD, Gertz EW. Myocardial lactate release during ischemia in swine: relation to regional blood flow. Circulation. 1990;81:1948-1958.
LeGrice IJ, Takayama Y, Holmes JW, Covell JW. Impaired subendocardial function in tachycardia induced cardiac failure. Am J Physiol. 1995;268:H1788-H1794.