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Canine Right and Left Ventricular Cell and Sarcomere Lengths after Banding the Pulmonary Artery By Michael M. Laks, M.D., Fred Morady, and H. J. C. Swan, M.B., Ph.D. Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017 ABSTRACT Canine hearts were fixed with glutaraldehyde at zero transmural pressure 17 to 48 weeks after main pulmonary arterial banding. Tissues were taken from the trabeculae carneae at the ventricular right base, right apex, left base, and left apex. They were placed in osmium tetroxide, embedded in Epon 812, stained with Azure II methylene blue, and sectioned at M fi. The mean cell lengths of the hearts with main pulmonary arterial banding were greatest at the right base, 105 ±5 fj, and left base, 103 ± 5.7 fx. (The means ± SE are given.) The mean cell length at the left apex was 95 ± 4 //, and that at the right apex was 92 ± 5 p. All were greater ( P < 0.001) than the cell lengths of normal hearts, 71 ± 1.5 ft. The mean sarcomere lengths of the right ventricle with main pulmonary arterial banding (right base, 2.04 ± 0.006 fj.; right apex, 2.18 ±0.004 fi) were less than those of normal hearts (right base, 2.41 ±0.006 fi; right apex, 2.46± 0.003 fj,). The mean sarcomere length of the left base with main pulmonary arterial banding (2.10 ±0.01 p) was less than the normal (2.16 ± 0.002 fji); however, the mean sarcomere length of the left apex with main pulmonary arterial banding (2.28 ±0.005 fi) was the same as the normal. With main pulmonary arterial banding, both the right and left ventricular cell lengths increased more at the bases than at the apexes, and the sarcomere • lengths decreased in the right base, right apex, and left base. ADDITIONAL KEY WORDS right ventricular base right ventricular apex • Previously reported quantitative determinations of cellular myocardial hypertrophy have been based solely on the estimation of the cross-sectional area of myocardial cells (13). No quantitative knowledge is available as to whether the length of the myocardial cell changes when the heart is stimulated to hypertrophy. We described a technique for stretching the myocardial fiber under constant conditions in the normal heart and for fixing this tissue with minimal shrinkage and distorFrom the Department of Cardiology and the Division of Medicine, Cedars-Sinai Medical Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90029. This work was supported in part by U. S. Public Health Service Grant HE-10382 from the National Heart Institute, Los Angeles County Heart Association Research Award 412 IC, and Ives Laboratories, Division of American Home Products. Received December 4, 1968. Accepted for publication March 19, 1969. Circulation Research, Vol. XXIV, May 1969 ventricular hypertrophy left ventricular muscle tion (4, 5). In addition, we described an increase in glycogen at the base as compared with the apex of the hypertrophied right ventricle (6). As an extension of these studies, we are reporting the changes in the cell and sarcomere lengths at the bases and apexes of the canine right and left ventricles produced by banding the pulmonary artery. Methods In five mongrel dogs weighing between 16 and 22 kg, right ventricular systolic pressures of 50 mm Hg or greater were produced by banding the main pulmonary artery. This technique has been described in detail previously (4, 5). Seventeen to forty-eight weeks after banding the pulmonary artery, the dogs were anesthetized with sodium pentobarbital, 27 mg/kg iv, and killed. The hearts were rapidly removed and fixed with glutaraldehyde at zero transmural pressure. Tissues were then taken from the trabeculae carnae at the bases and apexes of the right and left ventricles, placed in osmium tetroxide, 705 LAKS, MORADY, SWAN 706 •r.« Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017 CO CT5 Vol. XXIV, Ma> I5 Ctf.uUiton Rutir.b, 707 HYPERTROPHIED CELL AND SARCOMERE LENGTHS TABLE 1 Effect of Pulmonary Arterial Banding on Ventricular Weight Dog no. Right ventricle weight* (g/m=) Left ventricle weight* (g/m=) Right ventricular pressure (mm Hg) Normal 1 2 3 4 37.0 48.0 46.0 44.2 60.2 71.5 66.2 54.7 Pulmonary artery banding 5 6 7 8 9 78.7 50.2 70.5 60.1 82.3 69.9 55.5 88.5 94.2 65.8 20/2 25/4 22/3 20/2 72/4 50/3 55/3 58/3 80/4 'Expressed as grams per square meter of body surface area. Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017 embedded in Epon 812, sectioned at )i ft, stained with Azure II methylene blue, and then photomicrographed with a 4 by 5 camera fixed on a Zeiss Universal Light Microscope (Fig. 1). All measurements were made from high-contrast prints with a l,000x magnification for cell lengths and 4,000 X magnification for sarcomere lengths. The variability in the measurement of cell length due to stepwise configuration of intercalated discs was 2.3%. Statistical analysis was performed using both the standard f-test (7) and the rank sum method (8). A presentation of this method and a discussion of measurements of cell and sarcomere lengths in the normal canine heart have been reported (5). These animals were not considered to be in heart failure because there was no liver and lung congestion, pleural effusion, or ascites, and the end-diastolic pressure in the right ventricle was normal. All values are the means ± SEM. Results Ventricular Weights.—After banding the main pulmonary artery for 17 to 48 weeks, all of the right ventricular weights (Table 1) were greater than in the normal hearts (P < 0.01), and two of the five left ventricular weights were greater than in the control group. Cell Lengths.—After banding the main pulmonary artery, the mean cell lengths at zero transmural pressure were greatest at the right base, 105 ± 5 (i, and the left base, 103 ±5.7 (i, followed in length by the left apex, 95 ± 4 /x, and the right apex, 92 ± 5 /i. All were greater than those of normal hearts (right base, 67 ±2.5 fi; left base, 67±3.3 fi; left apex, 70 ±2,8 (i; right apex, 70 ±3.4 fi) Circulation Research, Vol. XXIV, May 1969 (P<0.01) (Table 2). Furthermore, in the hearts with pulmonary arterial banding, the cell lengths ranged from low normal to greater than normal; the percentages of cell lengths greater than 100 /A were 54% at the right base, 35% at the right apex, 45% at the left base, and 33% at the left apex, and all were significantly greater than the percentage in the normal hearts (right base, 16%; left base, 18%; right apex, 15%; left apex, 18%). Sarcomere Lengths.—After banding the main pulmonary artery, the mean sarcomere lengths at zero transmural pressure were 2.04 ±0.006 ft at the right base and 2.16 ± 0.004 fi at the right apex (Table 2) and were less than those of normal hearts (right base, 2.41 ±0.006 fi; right apex, 2.46±0.003 ft). However, after banding the main pulmonary artery, the mean sarcomere lengths were 2.10 ± 0.01 yu, at the left base and 2.22 ± 0.005 ix at the left apex, and were moderately, although significantly, less than the mean left ventricular sarcomere lengths of normal hearts (left base, 2.16 + 0.002 fi; left apex, 2.28± 0.005 ft) (P<0.001). Number of Sarcomeres Per Cell Length.— As previously described, the number of sarcomeres per cell length was computed by dividing each cell length by the mean sarcomere length in that region. After banding the main pulmonary artery, the mean number of sarcomeres per cell length (Table 2) was greatest at the right base, 53, followed by the left base, LAKS, MORADY, SWAN 708 TABLE 2 Statistical Data for Five Dog Hearts with Pulmonary Arterial Banding and Four Normal Hearts Sarcomere length Region Dog no. N Mean Cell length (ji) ±SEM N Mean Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017 Right apex 5 6 7 8 9 Five Dogs With Pulmonary Arterial Banding 2.18 109.1 159 22 0.003 64 2.40 71.3 0.010 19 85.6 2.20 145 0.003 18 131 2.06 0.003 97 2.15 97.5 0.005 27 Right base 5 6 7 8 9 114 52 174 67 140 1.84 1.96 2.16 2.02 2.12 0.004 0.005 0.004 0.005 0.003 30 26 27 20 26 117.7 102.9 98.4 101.4 103.0 Left apex 5 6 7 8 9 200 120 153 78 96 2.24 2.39 2.20 2.29 2.25 0.003 0.002 0.002 0.010 0.007 19 18 24 17 33 Left base 5 6 7 8 9 125 89 177 116 53 2.11 2.26 1.93 2.00 2.14 0.004 0.009 0.003 0.007 0.006 25 14 26 15 18 ±SEM Sarcomeres per cell length 12.7 7.8 10.8 50.0 29.7 38.9 8.8 45.4 7.8 8.8 8.7 7.0 9.7 64.0 52.5 45.5 50.2 48.6 93.7 108.1 76.3 95.7 95.6 7.6 13.6 7.8 9.8 6.4 41.8 45.2 34.7 41.8 42.5 92.4 94.9 104.0 108.9 110.9 8.3 11.6 10.9 9.1 7.2 43.6 42.0 53.9 54.5 52.1 Comparison Between Pooled Data Right apex Normal PAB P P 390 596 2.46 2.18 0.003 0.004 66 86 70.0 92.0 3.4 5.0 29.0 43.0 Right base Normal PAB P P 480 547 2.41 2.04 0.006 0.006 94 129 67.0 105.0 2.5 5.0 29.0 53.0 Left apex Normal PAB P P 464 647 2.28 2.22 0.005 0.005 92 111 70.0 95.0 2.8 4.0 31.0 43.0 Left base Normal PAB P P 411 560 2.16 2.10 0.002 0.01 68 98 67.0 103.0 3.3 5.7 31.0 47.0 PAB = pulmonary arterial banding. P = pooled data. 47, left apex, 43, and right apex, 43; and all were greater than the normal (right base, 29; left base, 31; left apex, 31; right apex, 29). In the hearts with pulmonary arterial banding, the percentage of sarcomeres per cell greater than 45 was 63% at the right base, 41% at the right apex, 41% at the left base, and 43% at the left apex. These percentages were significantly greater than in the normal hearts (right base, 7%; right apex, 1%; left base, 13%; left apex, 9%). Discussion Cell Lengths.—In dogs with banded pulmonary arteries, the discovery that the longest cell lengths were at the right base might be predicted by the law of Laplace: Tension or strain is equal to the product of pressure and radius. Therefore, with a pressure overload, Circulation Research, Vol. XXIV, May 1969 709 HYPERTROPHIED CELL AND SARCOMERE LENGTHS Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017 the greater strain or stimulus to hypertrophy would occur at the ventricular base which has a larger diameter than the apex. The calculated increase in the number of sarcomeres per cell length indicates that the increase in cell length is the result of adding more sarcomeres to the cell and not merely due to a stretching of the sarcomeres. We previously reported (6) an increase of glycogen adjacent to the intercalated disc, and this raises the question whether the locus for the addition of more sarcomeres may be at the intercalated discs. Since hypertrophy is a process by which the heart compensates, a study of the area of the intercalated disc in the failing heart may reveal a clue to the biochemical alterations in heart failure. The left ventricular cell lengths of dogs with pulmonary arterial banding were significantly longer than those of normal hearts; although this increase was less than that in the right ventricle. The participation of the left ventricle in the hypertrophy process cannot be attributed to the interventricular stimulus of pressure overload. The left ventricular volume appears to be increased after pulmonary arterial banding (9). Spann et al. (10) reported a moderate decrease in left ventricular norepinephrine content in cats with banded pulmonary arteries. Although we have no knowledge of the mechanism by which the left ventricular cells hypertrophy, the right and left ventricular myocardium may behave as a single structure in that a stress to one results in a hypertrophy of both. It is possible that a substance which has the property of producing hypertrophy may be released from the overloaded right ventricle and transported to the left ventricle. In the hearts with pulmonary arterial banding, the frequency distribution of cell lengths ranged from low normal to significantly greater than normal. Because of this extreme variability, we may deduce that the stimulus to hypertrophy is either nonuniform or the individual cells have a different capability of adding more sarcomeres. At present, it is not known whether myocardial Circulation Research, Vol. XXIV, May 1969 cells differ metabolically or anatomically from the cells with a normal length. Sarcomere Lengths.—The striking decrease in right ventricular sarcomere lengths after banding the pulmonary artery may be considered a reflection of a decrease in right ventricular compliance. This decrease in compliance may be simply the results of an increase in muscle mass. On the other hand, the study of Buccino et al. (11) pointed to an alteration in the myocardium per se. They demonstrated an increase in connective tissue as indicated by an increase in hydroxyproline in the right ventricles of cats with banded pulmonary arteries. The slight decrease in left ventricular sarcomere lengths may be explained by an increase in left ventricular connective tissue as reported by Buccino et al. (11) in cats with banded pulmonary arteries. References 1. KABSNEB, H. T., SAPHIB, O., AND TOPP, T. W.: State of the cardiac muscle in hypertrophy and atrophy. Am. J. Pathol. 1: 351, 1925. 2. LOWE, T. E., AND BATE, E. W.: Diameter of cardiac muscle fibers in the left ventricle in normal hearts and in the left ventricular enlargement of simple hypertension. Med. J. Australia 1: 467, 1948. 3. HARBISON, T. R., ASHMAN, R., AND LARSON, R. M.: Congestive heart failure: The relation between the thickness of the cardiac muscle fiber and the optimum rate of the heart. Arch. Internal Med. 99: 151, 1932. 4. LAKS, M. M., GARNER, D., AND SWAN, H. J. C : Volumes and compliances measured simultaneously in the right and left ventricles of the dog. Circulation Res. 20: 565, 1967. 5. LAKS, M. M., NISENSON, B. A., AND SWAN, H. J. C : Myocardial cell and sarcomere lengths in the normal dog heart. Circulation Res. 2 1 : 671, 1967. 6. LAKS, M. M., VAN D E VELDE, S., AND SWAN, H. J. C : Presence and location of glycogen in the hypertrophied right ventricle of the canine heart (absrr.). Clin. Res. 15: 211, 1967. 7. DIXONT, W., AND MASSEY, F.: Introduction to Statistical Analysis. New York, McGraw-Hill Book Co., 1957. 8. WILCOXON, F.: Individual comparison by ranking method. Biometrics Bull. 1: 80, 1945. 9. LAKS, M. M., GOLDBERG, D., AND SWAN, H. J. C : 710 LAKS, MORADY, SWAN Compliance and volume of the normal and hypertrophied canine ventricle (abstr.). Federation Proc. 25: 1966. 10. SPANN, J. F., JR., BUCCINO, R. A., SONTNENBLICK, E. H., AND BRAUNWALD, E.: Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hyper- trophy and heart failure. Circulation Res. 21: 341, 1967. 11. BUCCINO, R. A., HARMS, R., SPANN, J. R., JR., AND SONNENBLICK, E. H.: Connective tissue response in the development of experimental myocardial hypertrophy. Circulation 36 (suppl. I I ) : 11-77, 1967. Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017 Circulation Research, Vol. XXIV, May 1969 Canine Right and Left Ventricular Cell and Sarcomere Lengths after Banding the Pulmonary Artery MICHAEL M. LAKS, FRED MORADY and H.J.C. SWAN Downloaded from http://circres.ahajournals.org/ by guest on June 17, 2017 Circ Res. 1969;24:705-710 doi: 10.1161/01.RES.24.5.705 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1969 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/24/5/705 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation Research is online at: http://circres.ahajournals.org//subscriptions/