Trandolapril Decreases Prevalence of Ventricular Ectopic Activity in Middle-Aged SHR
Background Although severe arrhythmias are still a major problem in patients with left ventricular hypertrophy (LVH), the relationship between ventricular remodeling and its regression or prevention, and the prevalence of ventricular premature beats (VPB) or more sustained arrhythmias are still poorly explored in hypertensive heart disease.
Methods and Results Holter monitoring was used to quantify supraventricular premature beats and VPB and heart rate (HR) in middle-aged spontaneously hypertensive rats (SHR) and Wistar rats treated for 3 months with trandolapril (ACE inhibitor, 0.3 mg/kg per day). Hypertrophy and fibrosis were morphometrically determined. Statistical analysis was performed with the use of simple regression and multivariate data analysis (cluster and correspondence analysis). SHR have higher cardiac mass and fibrosis, more VPB, and a decreased HR. Cluster analysis demonstrated that trandolapril was only effective in SHR. Trandolapril significantly reduced cardiac hypertrophy, fibrosis, and VPB incidence and increased the HR. Simple regression analysis showed that VPB incidence correlated to both hypertrophy and fibrosis. Correspondence analysis evidenced a strong correlation between hypertrophy, fibrosis, and VPB, but only for severe hypertrophy, and the correlation disappeared for moderate hypertrophy.
Conclusions After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.
Clinical trials and experimental studies have repeatedly evidenced the beneficial effects of ACEI in hypertensive heart disease both in terms of survival and regression of LVH.
Epidemiological studies1 and clinical practice also have shown that the incidence of sustained arrhythmias, a major cause of sudden death, and ectopic beats were linked to the degree of LVH,2 3 even in patients without coronary insufficiency.4 Nevertheless, clinical trials showing the effects of ACEI and consecutive regression of LVH on the incidence of arrhythmias are still rather rare. VPB in hypertensive patients decreased after ACEI,5 whereas the same treatment may have a beneficial effect on the the prevalence of ventricular tachycardia and couplets in patients with congestive heart failure.6
For the moment, experimental data on the reduction of ectopic activity after ACEI are still rare. Only two studies showed that the ectopic activity, evaluated on an isolated rat heart preparation, decreased after ACEI.7 8
Our work is based on an original technique that involves the use of Holter monitoring in rats.9 Our purpose was to take advantage of experimental conditions to study the protective effects of ACEI in terms of arrhythmogenicity in an animal model, the rat, which is known to be resistant to atherosclerosis. The design of this study was achieved to analyze with the use of multivariate data analysis10 the different components at the origin of arrhythmias, namely fibrosis, hypertrophy, and changes in myocardial phenotype.11 The study was performed on middle-aged WST and SHR treated for 3 months with trandolapril, an ACEI.
For the first time, we have shown in conscious rats that the regression of ventricular arrhythmias not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved. Our model of Holter monitoring in conscious senescent SHR might be useful in correlating the response in myocardial structure to ACEI treatment with ventricular ectopic activity.
Our laboratory complies with the requirements of the Ministry of Agriculture and has been authorized to experiment on living animals according to Executive Order No. 87-848 of October 19, 1987.
Experiments were performed on 13-month-old male WST and SHR of the same origin (Iffa Credo). The rats were kept under similar housing conditions with a diurnal light cycle (lights on from 6 am to 6 pm), fed ad libitum with AO4C-10 pellets (Extra Labo, UAR), and divided into four experimental groups: untreated rats used as controls (SHR-C and WST-C, n=32 and 20, respectively) were given tap water containing the solvent for the ACEI trandolapril (stored at 10 mg/mL in 0.004N NaOH), and treated rats (SHR-T and WST-T, n=28 and 12, respectively) were given tap water containing trandolapril (0.3 mg/kg per day) for 3 months. The rats were 16 months old at the time of Holter monitoring. SBP was indirectly measured with use of the tail-cuff technique (Narco-Biosystems, BSR) twice monthly. After Holter monitoring, rats were killed, and blood samples were taken to measure plasma renin and ACE activities.12
Long-term ECG recording was carried out as previously described.9 After anesthesia was induced (50 mg sodium pentobarbital/kg body wt), three electrodes were implanted in the back of the rat. The leads were tunneled subcutaneously to the nape of the neck and then passed through a swivel-tethering system (Harvard Bioscience-Earling) that allowed the animal to move freely. After amplification, the one-channel ECG was recorded by a conventional Holter tape recorder (recorder model 2124, Ela Medical Inc) with a recording speed of 2 mm · s−1 adapted to the high heart rate of the rat. Monitoring procedure was started 24 hours later, the rat being placed in a special cage and provided with food and water ad libitum. During this protocol, 8 of 32, 6 of 28, and 4 of 20 of SHR-C, SHR-T, and WST-C, respectively, died. None of the treated WST died.
Quantification of Arrhythmias and Heart Rate
Printed recordings were used to quantify arrhythmias and were always analyzed by the same investigator in a blind manner. As previously described,9 the classic definition of arrhythmias in humans was used. The total number of SVPB and VPB were counted over the 24-hour monitoring. VPB were assigned to isolated ectopic beats, unifocal or multifocal; or repeated ectopic beats, couplets (two consecutive VPB), or more. The severity of ventricular arrhythmias then was assessed with the use of previous classifications13 14 and adapted to the high heart rate of the rat. The following definition was used: no VPB was class 0, infrequent isolated monofocal VPB (≤30 per hour), class 1; frequent monofocal VPB (>30 per hour), class 2; multifocal ectopic beats, class 3; couplets of VPB, class 4; triplets and nonsustained salvos of VPB (≤6 ectopic beats), class 5; and ventricular tachycardia, class 6. Heart rate was measured every 30 minutes over the 24-hour period. Each measurement was made on eight consecutive beats, and the mean heart rate was the average of all the measures in activity and the resting period. After elimination of artifacts, 81% of the Holter recordings were exploitable. The incidence of artifacts was the same in the four groups.
Myocardial Hypertrophy and Fibrosis Determination
After the rats were killed, the hearts were blotted and weighed. In a first group, the left and right ventricles and the two atria were dissected and weighed separately. In a second group, the heart was immersed in formalin for histomorphometric analysis of hypertrophy and fibrosis, as previously described.15 16 Briefly, two standardized transversal biventricular sections were stained with sirius red in the same bath and blindly studied by one investigator. Myocardial collagen was quantified with the use of an automated image analysis processor based on mathematical morphology software. Each field was transmitted by a gray level camera mounted on a light microscope or macroscope to the image analyzer and transformed into a 512×512-pixel digital image with 256 gray levels. Three sequential programs were used to study LVH and macroscopic, interstitial, and pericoronary collagen.
LVH and macroscopic collagen were determined in one field (×15 macroscopic magnification, final resolution of 30 μm per pixel). The whole left ventricular (LV) section was analyzed: the LV thickness and perimeter and the macroscopic collagen quantity and density (ratio between macroscopic collagen and total LV surface area) were quantified.
For the quantification of the interstitial collagen fraction in the subepicardium and subendocardium (magnification ×250 with a final calibration of 0.048 μm per pixel), only fields that did not contain pericoronary or scar collagen were analyzed. For each field, mathematical morphology sequence (top hat method) extracted all collagen structures and the corresponding myocardial surface area. The ratio between both measurements gave subepicardial and subendocardial collagen densities. In a second step, morphological operators (opening and closing functions) were allowed to transform all neighboring collagen structures as one object, whereas distant collagen structures stayed disconnected. Moreover, all small collagen objects in the field are “attracted” by the closer and bigger collagen object. These morphological transformations gave an underestimation of collagen component and could typically discriminate fields where the same collagen quantity was either widely distributed in tiny objects or poorly distributed in big objects. The ratio between collagen surface area and component number represented the interstitial collagen mean size.
For the quantification of pericoronary collagen, all coronary sections of the LV surface were analyzed at the same magnification as the interstitial collagen. The collagen components were extracted with the same image analysis sequence in the whole field, and the coronary lumen was extracted. The collagen was considered as pericoronary if it was related to a neighborhood degree, depending on the lumen dimension. The results were expressed as the pericoronary collagen surface area divided by the coronary lumen perimeter. Valuable data were obtained in 14 SHR-C, 12 SHR-T, 8 WST-C, and 12 WST-T. The third program was only performed on the two SHR groups.
Results are expressed as mean±SEM. In all cases, statistical significance was set at 5%. All data were compared with use of the nonpaired Scheffé’s F test after variance analysis except for nonparametric data (ie, incidence of premature beats), which were analyzed with use of the Kruskal-Wallis test. Simple correlations were performed by linear regression analysis with the least squares method. These statistical analyses were performed with the use of an analysis software (statview, Abacus Concepts, Inc). The same groups of rats (SHR-C, n=10; SHR-T, n=11) were used for all the simple correlations.
Subsequently multivariate data analysis (cluster and correspondence analysis) was performed.10 This analytical method is less restrictive than those previously used (with only one parameter studied in two groups) because it allows the simultaneous treatment of seven variables (SBP in mm Hg, HW in mg, SVPB and VPB number per 24 hours, and macroscopic, subendothelial, and subepicardial collagen densities) for four groups of rats (WST-C and WST-T, SHR-C and SHR-T). They were divided into classes corresponding to variable modalities in function of their repartition (median and quartiles). In this way, a final table was obtained for 34 rats and 29 classes (four for each parameter except for SVPB, which was divided into five classes). The specific data value of each rat was coded as being present or absent in the corresponding class. This final table was studied by hierarchical cluster and multiple correspondence analysis. The calculations created homogenous subpopulations of rats that were compared with use of the Mann-Whitney U test, and the correlation between the variables were studied with Spearman correlations. The calculations were carried out on BI software loginserm 1979/1987.
Effect of Strain: SHR Versus WST
Fig 1⇓ shows that in SHR-C, the SBP was higher than in WST-C during the 3-month period. In WST-C, a slight increase in SBP was observed from 128±3 at day 0 to 132±5 mm Hg at day 90 (P<.05). At the time the rats were killed, anatomic examination showed that neither WST-C nor SHR-C presented signs of failure. Plasma ACE activity was lower in SHR-C than in WST-C (66±3 versus 107±7 U/L, P<.001), but plasma renin activity was similar in both groups (13±1 versus 13±2 ng angiotensin I/mL per hour, P=NS).
Cardiac Hypertrophy and Fibrosis
Body weight of SHR was 70% of that of age-matched WST, but HW was higher in the SHR than in the WST (Table 1⇓). Both the LV and RV weights were elevated in SHR and the LV weight to right ventricular (RV) weight ratio did not change when compared with age-matched WST. The morphometric analysis showed that LVH was characterized by a thickening of the LV wall (from 2.23±0.08 mm in WST-C to 2.97±0.06 mm in SHR-C, P<.001) and an increased LV perimeter (from 35±0.9 to 46±0.7 mm, P<.001).
In SHR, the macroscopic collagen was more abundant than in WST (Fig 2a⇓ and 2b⇓ and Table 2⇓.) In SHR, the increase in fibrosis also was found for the subepicardial (+38%) and subendocardial (+45%) interstitial collagen densities (Table 2⇓).
Arrhythmias and Heart Rate
The incidence of SVPB was similar in both groups. VPB were nearly absent in the WST-C, whereas they were more than 60-fold more frequent in SHR-C (Table 3⇓). One SHR-C with 13 291 VPB was excluded from the calculations. In addition, as illustrated in Fig 3⇓, VPB were more complex in SHR-C than in WST-C. All the WST-C belonged to class 0, whereas 53% of the SHR-C belonged to class 3 or 4. No rats were found in classes 5 and 6.
A slight but significant bradycardia also was observed in SHR-C as compared with WST-C. This decrease in HR was similar whether the rats were in activity or at rest (Table 3⇑). Results also showed that in both groups, the HR was reduced at rest as compared with the activity period (P<.05 for WST-C and P<.01 for SHR-C).
Effects of Trandolapril
The slight increase of SBP observed in the 16-month-old WST-C was suppressed by trandolapril (Fig 1⇑). In SHR-T, the reduction in SBP was significant after 2 weeks and averaged −17% after 3 months. Nevertheless, at the end of treatment, SBP remained higher in the SHR-T than in WST-T. As expected, the treatment reduced plasma ACE activity; nevertheless, the reduction was more pronounced in WST-T (to 15±1 U/L, −85%, P<.001) than in SHR-T (to 39±4 U/L, −40%, P<.001). After ACEI, a significant increase in plasma renin activity was observed only in WST (from 13±1 ng angiotensin I/mL per hour in WST-C to 44±5 in WST-T, P<.001).
Cardiac Hypertrophy and Fibrosis
Trandolapril had no effect on body weight in either group and induced a significant regression of cardiac hypertrophy only in SHR (Table 1⇑). In SHR-T, the reduction of cardiac hypertrophy was higher in the atria (−49%) than in the right ventricle and left ventricle (−29% and −24%, respectively), but the LV weight to RV weight ratio was unchanged. Trandolapril did not affect the collagen content of the WST ventricles but significantly reduced fibrosis in SHR ventricles (Fig 2c⇑). In SHR-T, the macroscopic and pericoronary collagen densities (−39% and −28%) and the subepicardial collagen mean size significantly decreased (Table 2⇑).
Arrhythmias and Heart Rate
In both groups, the incidence of SVPB was unsensitive to the treatment. By contrast, one of the major results of this study was that ACEI nearly suppressed VPB in SHR-T, ventricular arrhythmias being ninefold less frequent than in SHR-C (Table 3⇑). As a result of trandolapril administration, the percentage of SHR in the classes of high-severity arrhythmias (classes 3 and 4) decreased from 53% to 23%.
After administration of trandolapril, mean HR did not change in the WST. In SHR-T, mean HR remained unchanged at rest but returned to the values similar to those recorded in WST during the activity period. Consequently, the difference in HR between activity and resting periods became higher in SHR-T than in SHR-C (Table 3⇑).
Simple Correlation Analysis in the SHR Group
The HR variations were only correlated to SBP changes (r=.59, P<.008, n=19). By contrast, the regression of cardiac hypertrophy was highly correlated to SBP reduction (r=.71, P<.001, n=21) and to myocardial fibrosis. The VPB reduction was correlated both to hypertrophy and fibrosis. The simple correlation analysis suggested that the ventricular arrhythmia regression was best correlated with the reduction of fibrosis. The VPB number was too scattered to allow covariance analysis (see Table 4⇓).
Multivariate Data Analysis
Such an analytical method allows the global description of systems that consist of many variables for sets of several groups of individuals (four groups of rats). In our study, we used two components of the multivariate data analysis: cluster analysis to research subpopulations and correspondence analysis to define the relationship among the variables in the four groups. In fact, we used only the rats in which the seven following parameters were available: SBP; HW; macroscopic, endocardial, and epicardial collagen densities; SVPB; and VPB.
Using cluster analysis, we found only three significantly distinct subpopulations (Fig 4A⇓): (1) SHR-C, (2) SHR-T, and (3) WST-C and WST-T, since there was no statistical difference between the parameters in WST-C and WST-T. This analysis allows the conclusion that trandolapril treatment was only effective in SHR (P<.001) and not in WST (except for the SBP at day 90). It further shows that despite the dramatic effects of trandolapril, the SHR-T remained different from WST-C (P<.001).
According to correspondence analysis (Fig 4B⇑), the highest values of most of the variables (SBP4, HW4, Coll4, VPB4, SVPB5; see Fig 4⇑ legend) were regrouped in the lower left quadrant. The lowest values (SBP1, HW1, Coll1 and Coll2, VPB1, and SVPB1) are in the right lower quadrant. Intermediate values were localized in the two upper quadrants. HW and Coll were strongly linked one to each other (r=.77, P<.01) and nearly distributed as a parabola, suggesting a linear relationship between both parameters. The same distribution also was observed for SBP. The subepicardial and subendocardial interstitial collagen densities presented noncoherent distributions (not shown). The highest incidence of both VPB (VPB4) was localized with the highest cardiac mass (HW4, HW >1600 mg) and highest fibrosis (Coll4, macroscopic collagen density >1.5%). Nevertheless, this relationship disappeared for the intermediate values: VPB3 colocalized with HW2 (upper right quadrant) and VPB2 with HW3 and Coll3 (upper left quadrant).
The main results of this study are the following. (1) The incidence of VPB as recorded for the first time in conscious rats is higher in middle-aged nonfailing SHR than in age-matched WST. (2) In SHR, long-term treatment with an ACEI reduces in a parallel manner ventricular arrhythmias, LVH, and fibrosis. (3) The reduction of ventricular arrhythmias is highly correlated with both myocardial hypertrophy and fibrosis in severe hypertrophy. Nevertheless, correspondence analysis suggests the role of additional factors, particularly during moderate hypertrophy.
The SHR is a genetic model of chronic overload with a lifetime elevated SBP and evolves toward failure with aging.17 In young adult SHR, myocardial hypertrophy consists mainly of LVH, and failure is preceded by a decrease in the LV weight to RV weight ratio and only occurs after 18 months.18 19 Middle-aged SHR used here were nonfailing hypertensive rats with no anatomic signs of failure and an LV to RV weight ratio similar to that of age-matched WST (Table 1⇑).
Fibrosis increases with age both in SHR and WST and is always greater in SHR.20 21 In this study, we found more than a twofold increase in the macroscopic collagen density in SHR as compared with WST. Middle-aged SHR present an important pericoronary and interstitial collagen density, as in older SHR.15 16 The morphometric analysis showed that the increase in the interstitial fibrosis mainly was due to an increase in the mean size of collagen scars in the subendocardium and to a multiplication of collagen scars in the subepicardium (Table 2⇑).
Recent evidence suggested an important role of peptide hormones, mainly angiotensin II (AII) and bradykinin, produced within the myocardium in regulating fibroblast collagen turnover.22 23 AII stimulates collagen synthesis and bradykinin decreases collagen synthesis and increases the collagenolytic activity. In vitro autoradiography studies showed a colocalization of ACE binding sites and areas of fibrosis and an association between AII-specific receptors and fibrosis extent.24 25
Several data suggest that in LVH, the intracardiac AII synthesis is activated.26 27 More recently, in renal or genetic hypertension in rats, an upregulation of AII-specific receptors also has been reported.28 Consequently, locally synthetized AII may contribute to the myocardial growth and fibrosis development that appeared in middle-aged SHR.
Our work was the first to show an increased number of ventricular arrhythmias in conscious middle-aged SHR compared with age-matched WST. These results confirm previous findings showing a higher propensity to arrhythmogenesis of isolated rat hearts from 14-month-old SHR.7 8 The information obtained with the use of Holter monitoring technique is more quantitative and closer to the in vivo situation than that obtained from an isolated heart preparation. As for clinical studies, arrhythmias can be quantified and classified according to their severity.13 14 Middle-aged SHR presented prognostic arrhythmias (Table 3⇑ and Fig 3⇑), since 53% of the SHR-C belonged to class 3 or 4, whereas all the WST-C belonged to class 0. According to the incidence of arrhythmias, middle-aged SHR closely resemble patients with LVH at New York Heart Association stage I. In a previous study, by using the same technique, we found a higher ectopic activity in senescent WST (24 months old) than in middle-aged WST (this study), suggesting that not only long duration of hypertension but also senescence increased the incidence of arrhythmias, thus extending previous conclusions of other clinical or experimental studies.29 30
In both groups, HR was significantly lower at rest than in activity. In SHR, mainly in activity, the mean HR was decreased compared with WST, as previously reported in 18-month-old SHR.31
Effects of Trandolapril
Cluster analysis (Fig 4A⇑) clearly showed that trandolapril had significant effects in SHR. This result is in agreement with a previous study showing that the interstitial collagen in WST was not affected by lisinopril treatment, when the same treatment normalized the fibrosis in SHR.32
In our study, trandolapril induced a significant but only partial regression of myocardial hypertrophy and fibrosis. Our protocol should be considered more as a treatment trial that prevents the worsening of LVH and fibrosis than as a prevention trial. Both hypertrophy and fibrosis were significantly reduced in SHR-T compared with SHR-C but remained higher than that observed in the WST groups.
In this study, ACEI reduced LVH by about 25% and fibrosis by about 40%. Trandolapril reduced perivascular reactive fibrosis and interstitial reparative fibrosis by decreasing the mean size of the collagen structures in the subepicardial interstitium (Table 3⇑). Previous studies on the effects of ACEI on LVH and fibrosis in young and senescent SHR clearly show that hemodynamic and hormonal factors are involved in the response of the myocardial structure to such a treatment.22 Treating SHR with a subhypotensive dose of ACEI had no effect on the SBP but prevented perivascular and interstitial fibrosis.33 These results suggest that the reduction of LVH depends mainly on hemodynamic factors, whereas that of the fibrosis has another origin.
We could speculate that in this study, the most likely mechanism for the reduction of fibrosis after trandolapril is a local inhibition of AII synthesis, since the middle-aged SHR have a lower plasma ACE activity that is less inhibited after trandolapril than in WST, whereas no effect on myocardial structure was observed in this group. Indeed, ACEI can inhibit the myocardial ACE activity and consequently decrease the intracardiac AII content.34 Since, as discussed above, the local synthesis and the effects of AII should be increased in SHR, it is not surprising that the effects of trandolapril were higher in SHR than in WST.
Trandolapril nearly suppressed ventricular arrhythmias but did not affect SVPB in SHR. The same treatment did not alter the electrophysiological phenomena of WST. A significant diminution of the incidence of ectopic beats has been observed in SHR after ACEI treatment.7 8 In a previous work, arrhythmias were quantified on isolated hearts, and the ACEI treatment was maintained for 11 months.7 In this case, the treatment could be considered more as prevention treatment compared with our protocol even if LVH and fibrosis were already present at 12 weeks.33 After trandolapril treatment, the percentage of SHR-T in class 0 increased from 47% to 77% and that in classes 3 and 4 decreased. Middle-aged SHR appear to closely resemble the clinical situation, ie, arterial hypertension in 60-year-old patients, and our results are similar to those observed in clinical protocols in moderate hypertension showing that an ACEI reverses the ectopic activity, reduces the severity of arrhythmias, and has no effect on the incidence of SVPB.5
Correspondence analysis (Fig 4B⇑) clearly shows that hypertrophy, fibrosis, and ventricular ectopic activity were highly correlated for severe hypertrophy since HW4, Coll4, and VPB4 are in the same quadrant. In this case the major determinant of ventricular arrhythmias is clearly the structural changes involved in the remodeling of the hypertrophied myocardium. For moderate hypertrophy, this relationship disappears and strongly suggests that the relationship between myocardial remodeling and ectopic activity is not as simple as previously discussed5 7 and that other factors could prevail in the genesis of ventricular arrhythmias.
Experimental evidence of a link between arrhythmias and a new myocardial phenoptype was recently provided in our laboratory.36 AII has several biological effects that could induce cardiac arrhythmias, at least in the LVH. It has been reported that AII increases the cytosolic calcium concentration,37 38 which may mediate cardiac arrhythmias.39
Our model of Holter monitoring in senescent SHR associated with a multivariate data analysis might be useful in correlating modifications of the response of the cardiovascular system to an ACEI treatment with reduction of ventricular arrhythmias. We showed that the relationship between LVH and fibrosis and ventricular ectopic activity is not as simple as has been suggested.5 We postulate that in severe hypertrophy, the genesis of arrhythmias is mainly dependent on structural alterations of LVH, while in moderate hypertrophy other factors are predominantly involved.
Prevention of severe arrhythmias is becoming a difficult task since the CAST Study.40 Our results suggest that the reduction of LVH is in fact the first step in treating benign arrhythmias. In addition, such a treatment has no toxicity as compared with other more classic antidysrhythmic drugs.
Selected Abbreviations and Acronyms
|ACEI||=||angiotensin-converting enzyme inhibitor|
|LVH||=||left ventricular hypertrophy|
|SBP||=||systolic blood pressure|
|SHR||=||spontaneously hypertensive rat(s)|
|SVPB||=||supraventricular premature beat(s)|
|VPB||=||ventricular premature beat(s)|
This work was supported by INSERM, Roussel-UCLAF, Fondation pour la Recherche Médicale, and Fondation de France (grant BS 1993). Dr Chevalier is a recipient of grant No. 90059 from Roussel UCLAF. The authors wish to thank D. Charlemagne and L. Rappaport for helpful discussions and rereading the article. We also thank F. Dowell for kind help in preparing the manuscript and D. Minet for his technical assistance.
- Received March 2, 1995.
- Accepted April 1, 1995.
- Copyright © 1995 by American Heart Association
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