Regression of Left Ventricular Hypertrophy With Captopril Restores Normal Ventricular Action Potential Duration, Dispersion of Refractoriness, and Vulnerability to Inducible Ventricular Fibrillation
Background Left ventricular hypertrophy (LVH) is associated with multiple cellular electrophysiological abnormalities, susceptibility to ventricular arrhythmias, and an increased risk of sudden death. Several pharmacological therapies have been shown to produce regression of hypertrophy, but the value of regression is unclear. The present study examines whether pharmacological regression of LVH has effects on the susceptibility to ventricular arrhythmia or the cellular electrophysiological abnormalities of LVH.
Methods and Results Rabbits underwent unilateral renal artery banding and contralateral nephrectomy to induce LVH or were placed in the control group. Both groups were studied 3 months later by in vivo and in vitro electrophysiological techniques. Banded rabbits had increased mean arterial pressure, increased left ventricular weight and wall thickness, increased dispersion of refractoriness, and lower ventricular fibrillation thresholds than control rabbits. Action potential duration and cell capacitance were also greater in the banded group. Additional rabbits were treated beginning 3 months after banding with either captopril (5 mg·kg−1·d−1) or vehicle added to their diet for an additional 3 months. These rabbits and age-matched controls were then studied by in vivo and in vitro electrophysiological techniques. In banded rabbits that received vehicle and were studied 6 months after banding, increased dispersion of refractoriness, a lower ventricular fibrillation threshold, and action potential prolongation persisted and were unchanged from animals studied 3 months after banding. Captopril, started 3 months after banding, caused regression of hypertrophy and normalization of the in vivo and in vitro electrophysiological abnormalities. Addition of captopril to the tissue bath during in vitro electrophysiological study showed no effect on cells from control or banded rabbits.
Conclusions Pharmacological regression of LVH with captopril normalizes the in vivo and in vitro electrophysiological abnormalities of ventricular hypertrophy and reduces the vulnerability to ventricular fibrillation in a renovascular model of LVH.
Left ventricular hypertrophy of any cause is associated with an increased risk of sudden cardiac death that is thought to be due to malignant ventricular arrhythmia. The increased vulnerability to ventricular arrhythmia appears to be the result of action potential prolongation and altered repolarization.1 2 These changes in APD and repolarization are not uniform3 and are associated with an increased vulnerability to inducible arrhythmia.4 5 6
Recent evidence in an animal model of LVH suggests that regression of LVH is associated with normalization of ventricular electrophysiology.7 That study used a constricting aortic band to produce LVH in cats. Regression of LVH was observed after removal of the aortic band and was associated with normal ventricular electrophysiology.7 This finding is compatible with normalization of hypertrophy-induced structural abnormalities after regression of LVH8 but is limited by important differences between the animal model and most clinical situations associated with LVH. In the aortic band model of LVH, a constricting aortic band was placed on the ascending aorta and produced an abrupt increase in afterload that is unlike systemic hypertension, in which afterload is thought to gradually increase. Furthermore, regression of hypertrophy was produced after surgical removal of the stimulus for hypertrophy. Such interventions are not generally possible in clinical situations. Thus, although potentially significant, our earlier study had important limitations.
The present study was therefore designed to determine whether pharmacological regression of LVH produced by ACEI would also reverse the electrical abnormalities associated with LVH. ACEI was chosen as a means of producing regression of LVH because these agents are widely used clinically and have no significant electrophysiological effect on in situ normal or hypertrophied hearts9 10 and because of evidence of decreased ventricular ectopy when chronic ACEI is used in a rat model of LVH.11
This study was carried out in conformance with the guidelines published by the American Heart Association, and the protocol was approved by the Lankenau Medical Research Center Animal Use Committee.
Adult New Zealand rabbits (1.8 to 2.2 kg) underwent unilateral nephrectomy with contralateral renal artery banding to produce LVH and then underwent in vivo and in vitro EPS 3 months later (LVH 3 month group). Control animals were matched for age and also underwent in vivo and in vitro EPS (control 3 month group).
Additional rabbits underwent unilateral nephrectomy with contralateral renal artery banding to produce LVH. Three months after banding, these rabbits were treated for an additional 3 months with either captopril at a dose of 5 mg·kg−1·d−1 or vehicle. This dose of captopril was selected on the basis of a prior report that doses in this range are well tolerated and are necessary to inhibit angiotensin II production in rabbits.12 These rabbits underwent in vivo and in vitro EPS 6 months after banding and 3 months after the start of captopril (LVH 6 month/captopril 3 month group) or vehicle (LVH 6 month group). Age-matched control rabbits received vehicle added to their diet for 3 months (control 6 month group).
Renal Artery Banding
Rabbits were anesthetized with sodium pentobarbital 30 mg/kg IV. Bilateral flank incisions were made and carried down by standard surgical techniques to the retroperitoneal space. The left renal artery was isolated, and a sterling silver clip was placed around this vessel. The clip had a preformed 0.5-mm gap that constricted the artery. After placement of the clip on the left renal artery, the right renal artery, vein, and ureter were ligated, and the right kidney was removed. The flank wounds were closed in layers by standard surgical techniques, and the animals were allowed to recover.
In Vivo EPS
α-Chloralose (50 mg/kg IV) was used for general anesthesia. Captopril was not administered on the day of the EPS. The rabbits were intubated and ventilated with a Harvard respirator. A femoral vein and artery were cannulated for drug administration and blood pressure monitoring, and a surface ECG was monitored. A sternotomy was performed, and a longitudinal incision was made in the pericardium. The heart was supported in a pericardial cradle. Transmural unipolar plunge electrodes were placed into the right ventricular outflow tract, right ventricular apex, LV anterior wall, LV posterior wall, and LV apex. A quadripolar pacing catheter (5-mm interelectrode spacing) was passed into the right ventricle via a cutdown on the right internal jugular vein. A second quadripolar catheter was inserted via a left atriotomy and positioned in the left ventricle.
EPS was performed with a Bloom stimulator (Bloom Limited) set to deliver constant-current rectangular impulses with pulse widths of 2 ms at twice diastolic threshold. Electrograms were amplified and recorded on a VR 12 physiological recorder (Electronics-for-Medicine). Ventricular ERPs were obtained with extrastimuli delivered at each of the unipolar plunge electrodes and the bipolar endocardial electrodes in 10-ms decrements after ventricular drive trains at the longest cycle length that consistently captured the ventricle. The ventricular drive cycle lengths were not significantly different between groups. The ERP was recorded as the longest S1-S2 coupling interval that failed to capture the ventricle and was measured with cathodal stimulation at each of the transmural unipolar plunge electrodes and with each of the endocardial electrodes, yielding three ERP measurements in the right ventricle and four in the left ventricle. Dispersion of ERP was defined as the maximum difference among all sites tested either within the right ventricle, within the left ventricle, or between the right and left ventricles.
Inducibility of ventricular arrhythmia was assessed by use of both of the endocardial catheters. With extrastimuli of twice threshold intensity, a 2-ms extrastimulus was delivered after 8 beats of ventricular drive. The method of extrastimulation used was the same as reported previously.4 An initial extrastimulus (S2) was set 250 ms after the pacing artifact of the last drive train beat and delivered in 10-ms decrements until refractoriness. If a sustained arrhythmia was not provoked, the S2 was set 20 ms later and a second extrastimulus (S3) was delivered. The S3 was initially set 250 ms after the S2 and then decremented by 10 ms until refractory or until induction of sustained arrhythmia. If a sustained arrhythmia was not induced, the S3 was set 20 ms later and a third extrastimulus (S4) was introduced. The S4 was initially set 250 ms after S3 and then decremented by 10 ms until refractory or until induction of sustained arrhythmia. A 3-second pause was given between drive trains. The end point of testing was the induction of a sustained arrhythmia (lasting >30 seconds or causing hemodynamic instability) or completion of the stimulation protocol. If an arrhythmia was induced, the testing was repeated to ensure reproducibility.
The endocardial catheter in the left ventricle was used to measure VFTs. For this purpose, we used the single-stimulus technique described previously.4 An extrastimulus was introduced in mid electrical diastole during ventricular pacing at an initial intensity of 2 mA (5-ms pulse width). The extrastimulus was decremented by 10 ms until refractoriness was reached. The current was increased in 2-mA increments, and electrical diastole was scanned as before. Current intensity was increased by 2 mA, and scanning continued until VF was induced. The arrhythmia was terminated after 15 seconds with a 5-J shock applied directly to the heart. Testing was repeated to ensure reproducibility. VFT, ERP, and inducibility of ventricular arrhythmia testing were all performed at the same drive train cycle length in each individual animal.
At the completion of the experiment, some animals were killed by VF that was induced and not terminated, followed by excision of the heart. Other animals were killed by rapid excision of the heart and several centimeters of ascending aorta. These hearts were used for cellular EPS.
Wall Thickness and Heart Weight Measurements
After electrical testing, the animals were killed and the hearts removed. The LV posterior wall thickness was measured with calipers at the level of the papillary muscles. Care was taken to measure the shortest transmural thickness of the posterior wall midway between the papillary muscles, perpendicular to the wall. The left ventricle was weighed after total heart weight was recorded, and both atria and the right ventricular free wall were excised.
For cellular EPS, single ventricular myocytes were isolated enzymatically. Rabbits that were not used in the in vivo experiments were heparinized (800 U/kg IV) and then anesthetized with ketamine (40 mg/kg IV)/xylazine (0.4 mg/kg IV). When deep anesthesia was achieved, the heart and several centimeters of proximal aorta were excised. Hearts from rabbits used in the in vivo experiments were excised at the completion of the in vivo study. All hearts were washed in cold bicarbonate-based Ca2+-free solution (in mmol/L: NaCl 125, KCl 3.5, KH2PO4 1.5, MgCl2·6H2O 1, NaHCO3 20, glucose 10) saturated with 95% O2/5% CO2 to clear the chambers of blood. After a quick blotting, the heart was weighed and then cannulated through the aorta and perfused with a modified Langendorff apparatus. The hearts were initially perfused with 500 mL Ca2+-free solution bubbled with 95% O2/5% CO2 at 37°C at a rate of 30 to 32 mL/min with a peristaltic pump. The heart was then perfused with 100 mL enzyme solution made by addition of 60 mg collagenase (type 2), 15 mg hyaluronidase, 100 mg BSA, and 0.375 g taurine to the Ca2+-free solution. The enzyme solution was gassed with 95% O2/5% CO2 and recycled. Ten minutes later, 7 mg protease XIV was added to the enzyme solution, and the heart was perfused for an additional 15 minutes. During perfusion, the heart surface was kept warm with a water jacket. At the end of perfusion, noncardiac tissue attached to the heart was trimmed, and the weight was subtracted from the total to obtain the net heart weight. The midlayer of the LV free wall was dissected out and minced in recovery solution (in mmol/L: potassium glutamate 80, K2HPO4 20, KCl 20, MgCl2·6H2O 5, K2EGTA 0.5, Na2ATP 2, Na-pyruvate 5, creatine 5, taurine 20, glycine 10, glucose 10, and HEPES 5) containing 0.5 mg/10 mL DNAse I. The myocytes were dispersed in KB solution by agitation, and the resulting cell suspension was filtered through 290-μm nylon mesh. Ten minutes after dispersion, cells were transferred to a HEPES-buffered 1-mmol/L Ca2+ Tyrode’s solution (in mmol/L: NaCl 137, KCl 5, MgCl2 1, CaCl2 1, glucose 10, HEPES 10; pH 7.4) and stored at 10°C. This procedure yielded 50% to 70% rod-shaped cells in normal rabbits. The yield in hypertrophied hearts was 20% to 40%. Cells were used for experiments within 8 hours after isolation.
In Vitro EPS
Microelectrodes were fabricated with a vertical pipette puller (model 730, David Kopf Instruments) and had a resistance of ≈50 MΩ when filled with 3 mol/L KCl; a HEPES-buffered 2-mmol/L Ca2+ Tyrode’s solution was used as bath solution. Cells were placed in a water-jacketed plastic chamber with a glass coverslip at the bottom that sits on the stage of a Nikon Diaphot inverted microscope. Solutions were pumped into the chamber with a peristaltic pump at a rate of 1 to 1.2 mL/min and removed by vacuum suction. Action potentials were recorded at 37±0.1°C by the conventional microelectrode technique in the bridge mode of Axoclamp-2A (Axon Instruments). Only cells with no spontaneous activity and resting potentials more negative than −70 mV were used. After microelectrode penetration, the cell was continuously stimulated by a 2-ms suprathreshold pulse repeated at 2 Hz. Action potential recordings were made with pClamp software (Axon instruments) with a sampling rate of 2 kHz. Whole-cell membrane currents were recorded at a temperature of 24±0.5°C by the whole-cell patch-clamp technique in the voltage-clamp model of Axopatch-1C (Axon Instruments). Patch pipettes were pulled from borosilicate glass tubing on a horizontal puller (P-80/PC, Sutter Instruments Co) and had a resistance of 1 to 2 MΩ when filled with pipette solutions. Cell capacitance was determined from the current transient induced by a hyperpolarization voltage stepping from −50 to −60 mV. The cell capacitance was calculated as the ratio of total charge (the integrated area under the current transient) to the magnitude of the pulse (10 mV).
Results are expressed in text, tables, and figures as mean±SD. Statistical analysis was performed with the True Epistat 4.0 statistical package (Epistat Services). Student’s t test was used for simple two-way comparisons (eg, body weight, heart weight, etc) between banded and control groups. Comparisons of electrophysiological parameters between banded and control groups were made with one-way ANOVA. Comparison of the relationship between dispersion of refractoriness and VFT was made with simple linear regression.
Rabbits banded to produce LVH and studied at 3 months after banding (LVH 3 month group) developed increased mean arterial pressure and LVH. Mean arterial pressure was 79±7 mm Hg in LVH 3 month rabbits versus 61±8 mm Hg in control rabbits (P<.05). LVH was manifest as an increase in LV weight (5.6±0.9 versus 4.2±0.5 g), LV weight/body weight (1.7±0.2 versus 1.3±0.1 g/kg), and LV wall thickness (0.43±0.05 versus 0.35±0.03 cm) (P<.05, LVH 3 month group versus control 3 month group, Table 1⇓). LVH was uniformly present in the 12 rabbits of the LVH 3 month group. The development of LVH was not associated with a significant change in ERP at any individual site within the right ventricle or left ventricle but was associated with a doubling of the dispersion of refractoriness between all sites (34±5 versus 16±5 ms, P<.05, LVH 3 month versus control 3 month group, Table 1⇓). LVH was also associated with an increased vulnerability to inducible VF, as evidenced by a significantly lower VFT (23±4 mA) versus control 3 month rabbits (39±7 mA, P<.05) with a single extrastimulus after an eight-beat drive train (Table 1⇓). Programmed stimulation with up to three extrastimuli did not induce sustained ventricular arrhythmia.
Cellular EPS showed prolongation of the action potential in cells isolated from the posterior LV of rabbits in the LVH 3 month group (Table 1⇑). APD90 was 190±23 ms in the hypertrophied myocytes versus 157±27 ms in control myocytes (P<.05). The capacitance of the LVH cells was also significantly increased compared with controls (182±47 versus 134±29 ms, P<.05), consistent with an increase in myocyte size. The resting membrane potential and action potential amplitude were not significantly different between the LVH and control cells. Addition of captopril (1, 10, and 100 μmol/L) to the perfusate had no significant effect on APD90 (Table 1⇑). Addition of captopril to the perfusate had no effect on cell capacitance, resting membrane potential, or action potential amplitude in either the LVH 3 month group or control animals (data not shown). Representative action potential tracings from these groups are shown in Fig 1⇓.
Rabbits banded to produce LVH that were studied 6 months after banding (LVH 6 month group) showed increased mean arterial pressure, LV weight, LV weight/body weight, and LV wall thickness compared with control rabbits (control 6 month group, Table 2⇓). The increase in these parameters was not significantly greater than had been observed in rabbits studied at 3 months after banding. Site-specific ERP was not significantly different, but dispersion of refractoriness between all sites was increased (34±5 versus 14±5 ms, P<.05, Table 2⇓), and there was an increased vulnerability to ventricular arrhythmia manifest as a lower VFT (21±3 versus 38±8 mA, P<.05) compared with control 6 month rabbits (Table 2⇓). None of the rabbits had inducible ventricular arrhythmia with programmed stimulation.
Electrophysiological evaluation of myocytes isolated from the posterior LV of rabbits 6 months after renal artery banding (LVH 6 month group) showed significant prolongation of APD (189±21 versus 162±26 ms, Table 2⇑) and increased cell capacitance (207±50 versus 154±35 ms) compared with control 6 month rabbits (P<.05) but no change in resting membrane potential or action potential amplitude (Table 2⇑). The magnitude of these abnormalities was similar to those observed in the LVH 3 month rabbits.
Captopril was effective in producing regression of hypertrophy in this animal model. Rabbits that underwent renal artery banding to produce LVH and 3 months later were treated with captopril (LVH 6 month/captopril 3 month group) had a lower mean arterial blood pressure (64±7 versus 80±9 mm Hg), lower LV weight (4.9±0.6 versus 5.3±0.6 g), lower LV weight/body weight (1.2±0.2 versus 1.5±0.1 g/kg), and lower LV wall thickness (0.37±0.03 versus 0.47±0.03 cm) than banded rabbits treated with vehicle (LVH 6 month group), which had persistent LVH (P<.05, Table 2⇑).
Regression of hypertrophy in the captopril-treated rabbits was associated with significantly less dispersion of refractoriness (14±5 versus 34±5 ms, Table 2⇑) and a higher VFT (35±8 versus 21±3 mA, Table 2⇑) than rabbits with persistent LVH (P<.05, LVH 6 month/captopril 3 month versus LVH 6 month group). Myocytes from captopril-treated rabbits did not show prolongation of APD (161±27 versus 189±21 ms) or increased capacitance (139±48 versus 207±50 pF) compared with banded rabbits treated with vehicle (P<.05 versus LVH 6 month group, Table 2⇑). The in vivo and in vitro electrophysiological parameters of the captopril-treated rabbits were not significantly different from those of the control 6 month rabbits (P>.05). Representative action potential tracings from these groups are shown in Fig 2⇓.
The relationship between dispersion of refractoriness and VFT is shown in Fig 3⇓ for all groups. VFT was inversely related to dispersion of refractoriness. The regression slope was statistically different from zero, with a two-tailed value of P<.001. The coefficient of codetermination statistic (R2) estimated that 97% of the variation in VFT could be explained by variation in dispersion of refractoriness (Fig 3⇓).
This study demonstrates that ACE inhibition with captopril produces regression of hypertrophy, normalizes APD, normalizes dispersion of refractoriness, and decreases vulnerability to inducible VF in an animal model of LVH. This is the first report to demonstrate that a pharmacological intervention will normalize any of these electrophysiological abnormalities. Furthermore, this is one of the first reports to link pharmacological regression of hypertrophy with a potentially clinically relevant benefit. Previous studies have not been designed to show a benefit beyond regression itself; thus, the value of regression has been unclear.
We hypothesize that any intervention that produces regression of hypertrophy will normalize ventricular electrophysiology. Previous studies used surgical methods to remove the stimulus for hypertrophy and reported either in vitro7 or in vivo13 normalization of electrophysiological abnormalities. The present study demonstrates normalization of both in vivo and in vitro electrical properties with a pharmacological method. The normalization of electrical parameters after either pharmacological or surgical methods to produce regression indicates that it is regression of hypertrophy per se, and not necessarily treatment with captopril, that is responsible for the normalization of electrophysiological parameters observed in our study.
Electrical abnormalities persisted in myocytes isolated from hypertrophied ventricles, cells that were no longer exposed to either circulating neurohumoral factors, electrolyte abnormalities, or increased afterload. This suggests that the electrical abnormalities of isolated, hypertrophied myocytes are independent of these factors. Similarly, the myocytes from captopril-treated rabbits had normal APD even after isolation, when they were no longer exposed to captopril. This suggests that normalization of APD was not due to a direct electrophysiological effect of captopril. Furthermore, captopril had no effect on APD when administered to isolated cells from rabbits with LVH at 3 months after banding. Other investigators using normal guinea pigs have also reported no change in APD after exposure to captopril.14 Thus, captopril does not appear to have direct electrophysiological effects that would explain the results of our study.
Prolongation of APD is the major cellular electrophysiological abnormality associated with LVH and has been observed in virtually every animal model to date.1 2 This abnormality is not uniformly distributed and is thought to be responsible for dispersion of refractoriness and increased vulnerability to ventricular arrhythmia.3 5 6 7 The exact ionic current or currents that are altered in response to hypertrophy are dependent on the model used. Conflicting reports are available about the direction and magnitude of change for almost every ion channel studied.2 A review of these data suggests that action potential prolongation in response to hypertrophy is the result of a summation of changes in the transient outward current (Ito) as well as the delayed and background rectifier currents (IK, IK1), among others.2 Regardless of the exact ion channel alterations, our data indicate that these changes are reversed by captopril in this model. Further work to identify the specific ion current changes induced by hypertrophy in this model and how they are affected by regression is in progress.
EADs are often observed in animal models of LVH and probably play an important role in the development of malignant ventricular arrhythmia.15 16 EADs are dependent on stimulation frequency and are most often observed at slower heart rates. We did not observe EADs in this study, possibly because of the stimulation frequency. Other studies have also used calcium channel agonists to provoke EADs,16 a technique that was not used in this study. Species variation, duration of hypertrophy, and other methodological differences could also contribute to the lack of EADs in our study. We did observe dispersion of refractoriness in rabbits with LVH, yet action potential prolongation was relatively uniform. This is probably because of the use of myocytes from only one LV site (the posterior wall) for action potential measurements, whereas refractory periods were measured at multiple sites. Further studies to examine action potential characteristics of isolated myocytes from other LV sites are ongoing.
LVH is observed both as a response to systemic arterial hypertension and in noninfarcted tissue as part of ventricular remodeling after myocardial infarction. Postinfarction hypertrophy, like the LVH seen in our renovascular rabbit model, is also associated with action potential prolongation, dispersion of refractoriness, and an increased incidence of inducible polymorphic ventricular tachycardia/VF.17 Postinfarction hypertrophy can be prevented by ACEI.18 We speculate that the lower incidence of sudden death observed in one post-MI trial of an ACEI may be due in part to prevention or regression of hypertrophy. A lower incidence of VF but not of monomorphic ventricular tachycardia was observed in post-MI patients treated with the ACEI trandolapril,19 as would be expected if ACEI prevented or reversed repolarization abnormalities.
A limitation inherent to animal studies is uncertainty with respect to how accurately the animal model reproduces the clinical problem being evaluated. The ventricular membrane electrophysiology of rabbits is similar in most respects to that of humans but is notable for a less prominent slow component of the delayed rectifier current (IKs). The renovascular model of hypertension in rabbits is similar to essential hypertension in humans in that this model produces gradual hypertrophy in the appropriate ventricle and the stimulus for hypertrophy is not introduced until the rabbits are mature. Furthermore, the main electrophysiological abnormalities observed in humans (APD prolongation, dispersion of refractoriness, and vulnerability to ventricular arrhythmia) are observed in this animal model and suggest that our results are clinically meaningful.
The relationship between VFTs and the risk of spontaneous ventricular arrhythmia is unclear. However, inducible VF is frequently found in patients whose only structural cardiac abnormality is LVH and who have symptoms suggestive of arrhythmia20 and has been used to risk stratify patients with hypertrophic cardiomyopathy.21 This suggests that the induction of VF may have significance. Furthermore, our data demonstrate that this in vivo electrophysiological parameter is abnormal in the setting of LVH and returns to normal with regression of hypertrophy. To the best of our knowledge, this is the first report that any in vivo electrophysiological parameter can return to normal after pharmacological treatment to cause regression of hypertrophy.
Dispersion of refractoriness was measured with unipolar transmural plunge electrodes and bipolar endocardial electrodes in this protocol. The use of unipolar transmural plunge electrodes does not allow determination of ERPs with high resolution but does allow assessment of dispersion of refractoriness. Recent data17 suggest that transmural gradients of refractoriness may be important in the vulnerability to arrhythmia due to postinfarction hypertrophy. We are studying the effect of LVH on transmural gradients of repolarization using arterially perfused transmural wedges. This method allows direct transmembrane recording of APD and should clarify whether large endocardial to epicardial differences in repolarization exist in this model.
Selected Abbreviations and Acronyms
|ACEI||=||ACE inhibition, inhibitor|
|APD||=||action potential duration|
|APD90||=||APD at 90% repolarization|
|ERP||=||effective refractory period|
|LVH||=||left ventricular hypertrophy|
|VFT||=||ventricular fibrillation threshold|
The authors wish to thank Rose Marie Wells and Nicole Ewing for their assistance in the preparation of the manuscript.
- Received December 12, 1996.
- Revision received February 21, 1997.
- Accepted March 2, 1997.
- Copyright © 1997 by American Heart Association
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