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Myocardial High Energy Phosphate Stores in Cardiac Hypertrophy and Heart Failure By Peter E. Pool, M.D., James F. Spann, Jr., M.D., Robert A. Buccino, M.D., Edmund H. Sonnenblick, M.D., and Eugene Brounwold, M.D. With the Technical Assistance of Shirley C. Seogren Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 ABSTRACT The aim of this study was to determine whether the impairment of contractility in the myocardium obtained from hypertrophied and failing hearts is due to a decreased store of energy and whether an imbalance exists between energy production and energy utilization in these hearts in vivo. Right ventricular hypertrophy and right ventricular failure were produced in cats by constriction of the main pulmonary artery. Concentrations of creatine phosphate (CP) and adenosine triphosphate (ATP) were determined in samples removed from the right ventricles of these animals during life and in papillary muscles isolated from these same hearts. The papillary muscles from the cats with hypertrophy and failure exhibited depressed intrinsic contractility. The stores of ATP were normal in both the ventricular muscles and the papillary muscles in animals with hypertrophy and failure. Although the stores of CP were significantly depressed in the right ventricles of these animals, the stores had increased toward normal in papillary muscles isolated from these same hearts in vitro. The finding of normal energy stores in the papillary muscles from animals with hypertrophy and failure indicates that their intrinsically depressed contractility cannot be due to reductions of their energy stores in vivo such as were found in the samples from the ventricular wall. The differences between high energy phosphate stores in failing heart in vivo and these stores as they are replenished in vitro also indicate that the in vivo depressions are secondary to an imbalance between energy production and energy utilization in the overloaded, hypertrophied and failing heart. ADDITIONAL KEY WORDS creatine phosphate creatine energy metabolism energetics • A major unresolved question concerning the mechanism of heart failure is whether a specific biochemical abnormality is responsible for this condition. Numerous investigations of this question have involved the study of patients with naturally occurring decompensation as well as animals with experimentally produced forms of heart failure. At various times it has been suggested that defects exist in energy production (1-4), energy storage (5-9), and energy utilization (10, 11). On the other hand, other studies have suggested that these three basic metabolic From the Cardiology Branch, National Heart Institute, Bethesda, Maryland 20014. Accepted for publication July 17, 1967. CircuUuon ReiMrcb, Vol. XXI, StpHrattr 1967 adenosine triphosphate right ventricular wall cat papillary muscle functions are entirely normal in heart failure (10, 12, 13). Furthermore, when evidence for specific defects in energy metabolism was obtained, it was unclear whether the observed defect was causally related to the heart failure state. Considerable information can be obtained by measuring the myocardial high energy phosphate stores, creatine phosphate (CP) and adenosine triphosphate (ATP). While such determinations do not provide a complete description of the energy metabolism of cardiac muscle, they do permit an assessment of the balance between energy production and energy utilization. However, until recently, it has been difficult to measure myocar365 366 POOL, SPANN, BUCCINO, SONNENBLICK, BRAUNWALO Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 dial high energy phosphate stores with accuracy because of the great lability of these stores. The importance of extremely rapid freezing techniques in the accurate determination of these energy stores was first demonstrated by Wollenberger and associates in 1958 (14). Subsequently, modifications of this technique (15) and improved analytic methods (16-18) have made possible the accurate determination of these stores. The development of a technique which allows detailed evaluation of the contractile function of the myocardium obtained from the hearts of animals with ventricular hypertrophy and heart failure combined with modern techniques for detennining energy stores provided a unique opportunity for studying the question of a specific biochemical defect in heart failure. It was the aim of this study to determine whether the recently demonstrated impairment of cardiac contractility in the myocardium obtained from hypertrophied and failing hearts (19) is due to a decreased store of energy and whether an imbalance between energy production and energy utilization exists in these hearts in vivo. Methods Right ventricular hypertrophy and right ventricular failure were produced in adult cats by constriction of the main pulmonary artery. Twenty-one to 90 days following operation, circulatory dynamics was evaluated by means of right heart catheterization under barbiturate anesthesia. On the basis of measurements of the right ventricular end-diastolic pressure, cardiac output, and arteriomixed venous O2 difference, as well as the findings provided by autopsv, it was possible to separate animals with hypertrophy from those with overt heart failure (19). Following hemodynamic study in the intact animal, the chest was opened widely and samples of right and left ventricular myocardium were obtained with a 6-inch mastoid rongeur, while intermittent positive pressure ventilation was provided via a tracheostomy. Care was taken to insure a stable hemodynamic state and an adequate O2 supply at the time of the biopsy; at this time the arterial blood O ; content was not different from that of normal cats, and in the few cats in which it was measured, arterial (X saturation was greater than 90%. The sample from the second ventricle was analyzed only if obtained within 3 sec of the sample from the first ventricle. The samples were obtained from the free wall of each ventricle, and those from the right ventricle wert within 5 mm of the base of the papillary muscle. All of the samples were through the ventricular wall and usually tissue from the right ventricle was removed first. The specimens, weighing an average of 22 mg, were frozen in liquid nitrogen within 0.5 sec. After these specimens were obtained, the hearts were rapidly extirpated and right ventricular papillary muscles were isolated. These were placed in a myograph in Krebs solution at 26°C (17), continuously aerated via a sintered glass gas dispersion tube with 95% O25% CO2, and allowed to equilibrate for 30 min while being stimulated to contract isometrically at a frequency of 12/min at low resting tensions. Following determination of the active length-tension curve, each muscle was stimulated to contract isometrically at the top of this curve for an additional 30 min, and then was rapidly frozen between contractions by quickly removing the muscle bath and replacing it with a beaker of 2-methylbutane (isopentane) previously cooled in liquid nitrogen to —150° to —160°C. This procedure freezes the muscle without further contraction. The papillary muscles and samples removed from the myocardium were stored in liquid nitrogen. On the day of assay, each tissue was pulverized at —50°C as previously described (18), and perchloric acid extracts were prepared. CP and inorganic phosphate (Pj) were determined by the phosphomolybdate method of Fiske and Subbarow (20) as modified by Furchgott and De Gubareff (16), creatine concentrations by the a-naphthol-diacetyl method of Ennor and Rosenberg (21, 22), and ATP by a modification of the firefly luminescence method of Strehler and McElroy (23). Modifications of these procedures have been described previously in detail (17). Statistical tests of the significance of the difference between group means and paired samples (right ventricle vs. papillary muscle) were made by the appropriate f-tests (24). Results The extent of the elevation of right ventricular weight, right ventricular systolic and end-diastolic pressures and the absence of an increase in ventricular water content in the animals with right ventricular hypertrophy and heart failure are presented in detail elsewhere (19). SAMPLES OF VENTRICULAR DURING LIFE MUSCLE OBTAINED Right Ventricle—In. specimens of right venRtitfcb, Vol. XXI, Stpttmht 1967 367 MYOCARDIAL ENERGY STORES IN HEART FAILURE CREATINE ATP PHOSPHATE • - Control - 17 E 3 - RVH - 10 E 3 - CHF - 8 .2? o E o E Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 ,02 J -p<.05 J p<.01 -N.'s. - ' FIGURE 1 In vivo right ventricular high energy phosphate stores in normal cats and cats with right ventricular hypertrophy (RVH) and congestive heart failure (CHF). Units for ordinates are fimoles per gram wet weight of heart muscle. Vertical lines with cross bars = ± 1 SEM. tricle obtained from cats in congestive heart failure (CHF), levels of ATP and Pf did not differ significantly from those found in right ventricular tissue obtained from normal animals or animals with right ventricular hypertrophy (RVH) (Fig. 1). On the other hand, the concentrations of both total creatine and CP were significantly reduced; the total creatine averaged 15.5±0.6 (SEM), 12.5± 0.9 and 9.7 ±0.6 /nmoles/g respectively in the normal, RVH and CHF groups, while the CP averaged 7.22 ±0.49, 5.42 ±0.45 and 4.15 ± 0.40 fimoles/g in these three groups. The fraction of total creatine present as CP was essentially identical in all three groups, averaging 46%, 43%, and 43% respectively (Table 1). Left Ventricle.—As in the right ventricle, average concentrations of ATP and Ps were similar in the left ventricles of animals in all three groups. Both total creatine and CP were significantly lower in the CHF group than in the normal and RVH groups (P < .05). However, no significant differences in creatine and CP concentrations were observed between the normal and RVH groups. The fraction of total creatine present as CP was again similar in all three groups, averaging Circulation Research, Vol. XXI, September 1967 45% in hearts of control animals, 52% in the RVH group and 49% in the CHF group. PAPILLARY MUSCLES Other papillary muscles from the same groups of animals as those used for biochemical analysis were subjected to detailed analysis of myocardial mechanics (19); the maximum velocity of shortening of the unloaded muscle (Vmilx), the rate of development of tension and the peak isometric tension were depressed. However, it was considered necessary to obtain an index of the mechanical performance of the muscles actually subjected to analysis of high energy phosphate stores. The isometric tension at the peak of the active length-tension curve (P o ) was therefore determined in each muscle. This variable averaged 5.2 ±0.8 g/mm2 in the muscles removed from 7 control animals, and was significantly lower in the 9 muscles obtained from animals with hypertrophy, in which it averaged 1.8 ± 0.4 g/mm2, and in the 7 muscles obtained from animals with heart failure, in which it averaged 1.1 ± 0.5 g/mm2. As observed in the biopsies of the right ventricular wall, there were no significant dif- 368 POOL, SPANN, BUCCINO, SONNENBLICK, BRAUNWALD TABLE 1 Rkht ventricle Ounolei/g) Eipt 8 g 10 n 12 Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 13 14 25 26 27 28 29 30 31 57 58 60 61 62 65 MEAN ±1SE 4 7 8 9 11 12 14 17 31 32 34 MEAN ±lSE 5 6 10 13 16 20 21 28 29 30 MEAN ±lSE Cr CP ATP 17.8 16.4 13.8 18.6 17.5 18.4 21.4 15.1 15.0 13.6 12.5 14.2 14.0 15.0 .16.9 14.4 17.2 13.8 12.4 12.8 15.5 0.6 7.35 7.70 6.76 10.20 9.36 4.61 4.61 3.22 3.67 4.91 Control 4.43 3.42 5.50 6.12 6.40 11.80 9.13 5.85 4.94 4.34 7.29 5.75 4.96 5.14 4.73 4.95 5.51 3.53 3.16 4.52 2.78 4.23 3.34 6.45 7.54 6.55 5.40 6.26 5.83 7.04 5.71 6.27 5.26 2.94 4.37 2.22 6.11 4.05 5.89 7.22 0.49 5.02 5.13 0.22 2.58 4.10 0.32 9.6 8.2 11.0 14.4 13.4 13.6 12.5 14.7 8.4 15.8 16.4 12.5 0.9 3.52 3.71 4.55 6.04 6.35 5.69 Hypertrophy 3.62 3.70 4.54 3.98 4.55 3.96 5.86 5.16 3.94 5.86 5.21 5.59 5.52 4.71 6.11 8.01 5.42 0.45 5.08 5.41 5.41 7.54 5.13 0.37 7.69 3.66 3.76 3.47 4.67 0.45 3.73 5.99 Failure 6.48 4.61 4.21 3.21 4.29 5.65 2.26 4.45 4.99 3.21 4.15 0.40 3.67 6.56 2.62 5.69 5.05 6.68 5.06 0.55 5.54 10.60 3.22 3.36 2.79 3.19 4.80 1.02 12.7 9.6 9.9 10.0 11.1 8.7 5.5 9.0 10.8 9.6 9.7 0.6 Pi Cr 22.3 15.8 15.5 17.8 14.1 19.8 20.9 18.4 17.6 18.0 13.6 16.5 17.0 16.0 18.4 18.2 16.9 14.7 18.7 17.4 0.5 12.1 16.1 14.9 14.0 18.0 14.9 13.8 25.0 15.8 22.7 20.4 17.0 1.3 13.1 11.2 14.8 11.2 12.3 11.8 12.7 12.2 12.7 9.8 12.2 0.4 Left v(mtrlcle (junol e»/g) ATP CP Pi 8.09 10.90 9.26 7.97 8.82 11.10 10.40 5.24 6.13 3.93 4.42 6.10 5.50 6.91 3.94 4.89 6.77 3.76 4.71 5.16 7.70 5.49 4.98 5.16 4.74 7.30 5.77 4.29 5.74 5.26 6.26 5.87 6.73 6.36 4.46 7.23 7.85 0.68 5.76 0.31 5.32 0.38 6.13 8.99 4.30 6.13 3.56 8.59 7.79 8.81 4.81 7.20 2.66 5.09 14.20 8.46 7.74 7.57 6.59 6.08 7.09 8.78 1.06 6.09 6.26 0.55 5.04 5.37 0.80 4.69 7.77 5.95 5.32 6.80 5.06 4.36 5.10 4.58 5.74 8.81 4.79 4.92 6.34 8.66 3.79 6.55 11.50 3.38 5.91 0.75 5.17 6.04 0.55 4.66 5.79 1.09 Cr = creatine; CP = creatine phosphate; ATP = adenosine triphosphate; P, = inorganic phosphate. CircuUuon Rtsetrcb, Vol. XXI, Septtmbtr 1967 MYOCARDIAL ENERGY STORES IN HEART FAILURE 369 10 r • - Control-7 2 - RVH - 5 E3 - CHF - 7 8 6 O Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 0 PAPILLARY MUSCLE RIGHT VENTRICLE FIGURE 2 ATP stores in the right ventricle in vivo are compared with those found in papillary muscles isolated from the same hearts and studied in vitro. Abbreviations and symbols as in Figure 1. 10 D - Control - 7 E3 - RVH - 5 E 3 - CHF - 7 § ih 2 5 RIGHT VENTRICLE PAPILLARY MUSCLE DIFFERENCE (PM-RV) FIGURE 3 Creatine phosphate stores in the right ventricle in vivo are compared iirith those in papillary muscles isolated from the same hearts and studied in vitro. Difference is between CP concentration in the papillary muscle and that in the right ventricle. PM =: papillary muscle; RV = right ventricle; other abbreviations and symbols as in Figure 1. Circulation Research, Vol. XXI, September 1967 370 POOL, SPANN, BUCCINO, SONNENBLICK, BRAUNWALD TABLE 2 Expt CP (^moles/g) RV PM TABLE 3 CP ATP RV PM PM Kipt. Control A B C D E F G MEAN ±lSE 9.13 7.29 6.55 6.46 5.89 7.04 5.10 6.78 0.52 9.27 7.44 8.00 8.08 5.60 7.40 6.26 7.44 0.50 4.96 5.51 5.71 5.26 5.02 5.75 5.16 5.34 0.13 5.00 5.45 6.18 5.25 4.23 6.52 4.46 5.30 0.34 4.5 6.4 3.5 6.0 7.3 6.9 1.8 5.2 0.8 Hypertrophy Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 H I J K L MEAN ±lSE 6.42 4.71 6.11 2.46 4.95 4.93 0.78 9.98 6.65 7.28 4.37 8.35 7.33 1.04 5.54 5.41 5.41 5.16 4.89 5.28 0.13 8.35 5.85 6.01 4.46 5.10 5.95 0.59 4.3 0.8 2.2 1.7 3.0 2.4 0.7 5.05 6.60 5.29 4.32 4.26 5.61 5.38 5.22 0.33 5.97 5.84 4.87 4.82 3.58 4.90 6.15 5.16 0.37 0.3 2.7 0.5 0.5 0.7 0.1 3.1 1.1 0.5 Failure M N O P Q R S MEAN ±lSE 4.99 6.36 3.87 3.45 4.85 4.65 2.69 4.41 0.49 7.76 12.30 7.06 5.06 8.03 554 7.52 7.61 0.96 RV = right ventricle; PM = papillary muscle. ferences among the ATP concentrations in the papillary muscles obtained from the three groups of animals, these values averaging 5.30 ±0.34, 5.95 ±0.59 and 5.16 ±0.37 ^.moles/g in muscles obtained from control cats and those with hypertrophy and heart failure respectively (Fig. 2). However, in contrast to the differences in concentrations of CP observed in right ventricular wall, no differences in these concentrations were observed in the three groups of papillary muscles (Table 2) (Fig. 3). COMPARISONS BETWEEN VENTRICULAR WALLS AND PAPILLARY MUSCLES No significant differences were observed between the ATP concentrations of the right ventricular wall and the papillary muscles A B C D MEAN ±lSE ATP l RV PM Hypertrophy-Resting 7.10 11.40 2.53 7.59 3.78 5.90 10.60 6.42 4.96 8.90 1.24 1.48 RV PM 5.75 6.65 5.21 5.54 5.79 0.36 5.83 5.56 5.90 4.54 5.46 0.36 RV = right ventricle; PM = papillary muscle. obtained from the same ventricles (Fig. 2). However, the CP concentrations were significantly higher in the papillary muscles; in the control animals this difference averaged 0.7 ±0.3 /xmoles/g, which was equivalent to ]0$ of the right ventricular concentration (Fig. 3). In the animals in the RVH and CHF groups the differences between CP concentration in papillary muscles andrightventricles were significantly greater than in the control group. In the RVH group this difference (2.4 ±0.5 ^moles/g) averaged 49$ of the right ventricular concentration, while in the animals with CHF, this difference (3.2 ± 0.7 //.moles/g) averaged 73$ of therightventricular concentration (Table 2 and Fig. 3). To determine whether the energy stores were related to the mechanical activity of the papillary muscles, the right ventricles and papillary muscles from a separate group of four animals with hypertrophy were studied. In this group, however, the papillary muscles, following 30 min of equilibration in vitro with stimulation 12 times/min, were allowed to rest for 30 min instead of being stimulated at a rate of 12/min. In this experiment, there was an even greater difference between the CP concentrations in the papillary muscles and the right ventricles (3.9 ±0.7 /xmoles/g) (Table 3) than that which was found when the contracting papillary muscles from cats with hypertrophy were compared to their right ventricles (2.4 ± 0.5 ^imoles/g) (Table 2). Discussion The objective of this investigation was to determine whether (1) an abnormality in Circtlation Rtiarcb, Vol. XXI, Stfitmttr 1967 MYOCARDIAL ENERGY STORES IN HEART FAILURE Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 myocardial energy stores occurs in cardiac hypertrophy and congestive heart failure; (2) the impairment of myocardial contractility in these states can be attributed to a depression of myocardial energy stores; and (3) an imbalance exists between energy production and energy utilization in failing and hypertrophied hearts. While ATP stores were maintained, a significant depression of CP concentrations occurred in the right ventricles of cats in the RVH and CHF groups. Although in one earlier study, such depressions of energy stores in chronic experimental congestive heart failure were not observed (10), the study was made before the general availability of the present, more accurate methods for measuring these compounds. However, the recent findings of Fox et al. (8) in dogs with chronic congestive heart failure and those of Feinstein (7) in the failing heart of the guinea pig are in general accord with ours. It is interesting, however, that in these studies (7, 8), modest depressions of ATP stores were also reported, while we found no changes in the concentrations of this compound, despite the presence of moderately severe ventricular hypertrophy and failure. Perhaps in the presence of more severe or prolonged stresses, these stores might be reduced. Fox et al. (8) found no changes in CP, ATP or creatine in the right ventricles of dogs with right ventricular hypertrophy without failure; we observed a significant depression both of total creatine and CP in cats with simple right ventricular hypertrophy, and Minton et al. (11) made similar observations in rats with cardiac hypertrophy. It is possible that the absence of significant changes in energy stores in the hypertrophied hearts reported by Fox et al. was due to a lesser degree of hypertrophy, although this was not evaluated in their study. In an earlier study from this laboratory Chidsey and associates (25) reported that cardiac CP and ATP stores were not depressed in patients with congestive heart failure. However, the interpretation of this finding is limited by the fact that the hypertrophied right CircmUHtm Rutrcb, VoL XXI, Stpumbtr 1967 371 ventricles in patients with tetralogy of Fallot served as controls. The depressions of CP and creatine stores noted in the left ventricles of the animals with primary right ventricular failure suggests( that the left ventricle may also be susceptible to the biochemical stresses imposed on the right ventricle if they are severe enough. Similar effects of right ventricular failure on the left ventricle have already been demonstrated both, hemodynamically and biochemically (10, 26-28). From the results of our studies on papillary muscles, it is clear that the depression of myocardial contractility found in hypertrophy and congestive heart failure and defined as a depression in both the maximum force (P o ) and intrinsic speed of contraction (V mai ) of the myocardium (19) is not a function of decreased energy stores. This finding correlates with the observation of normal oxidative phosphorylation in mitochondria isolated from these hearts studied in vitro (29). Although the mechanical function of these muscles obtained from failing and hypertrophied hearts was depressed throughout the experiment, energy stores were "restored" from the low in vivo levels to levels equal to those observed in papillary muscles obtained from normal cats (Fig. 3). Although it was found impossible to determine high energy phosphate stores in the papillary muscle in vivo because the muscle cannot be excised rapidly under physiologic conditions, it is not likely that its in vivo energy stores would be different from those found in the specimen of the right ventricle, which was taken within 5 mm from the origin of the papillary muscle. In addition, since it has been shown that the papillary muscles obtained from hypertrophied and failing hearts undergo the characteristic anatomic and physiologic changes of these conditions (19), it is expected that they also participate in the biochemical changes occurring in the remainder of the hypertrophied and failing heart. In hypertrophied and failing hearts the small normal differences between CP concentrations in the in vivo right ventricle and 372 POOL, SPANN, BUCCINO, SONNENBLICK, BRAUNWALD Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 isolated papillary muscle are significantly larger. Hochrein and Doling (30) have shown that increasing work alone in the intact heart may lower CP stores. In the in vitro papillary muscles in the present study, CP levels are higher than in vivo, which is consonant with the reduced work load in vitro as compared to that found in vivo. This reduction in work load in the hypertrophied and failing muscle is accompanied by a greater increase in CP levels than is found in normal muscles. Taken together these findings would indicate that there is an imbalance between energy production and energy utilization in the heart, and that this may be augmented in the presence of hypertrophy and failure. Whether this is due to an excessive increase in energy utilization or an inadequate increase in energy production cannot be answered at this time. Nevertheless, this imbalance occurs despite the normal in vitro function of mitochondria prepared from these hearts (29). In conclusion, it was observed in this investigation that reductions in myocardial energy stores exist in the presence of moderately severe degrees of ventricular hypertrophy in vivo and that these reductions are more marked in the presence of heart failure. The papillary muscles from these same hearts exhibited depressed contractility. However, the finding of normal energy stores in these papillary muscles indicate that their intrinsically depressed contractility cannot be due to the reductions of their energy stores. The differences between high energy phosphate stores in failing heart muscle studied in vivo and in vitro also indicates that the in vivo depressions are secondary to an imbalance between energy production and energy utilization in the overloaded, hypertrophied and failing heart. Acknowledgment The assistance of Nancy Dittemore, Robert M. Lewis, and Richard McGill is gratefully acknowledged. tion in sarcosomes from experimentally-induced failing rat heart. Proc. Soc. Exptl. Biol. Med. 117: 380, 1964. 2. 3. 4. 5. 6. 7. 1. ARGUS, M. F., ARCOS, J. C, SABDESAI, V. M., AND OVERBY, J. L.: Oxidative rates and phosphoryla- Some metabolic characteristics of mitochondria from chronically overloaded, hypertrophied hearts. Exptl. MoL Pathol. 2: 251, 1963. SCHWARTZ, A., AND LEE, S.: Study of heart mitochondria and glycolytic metabolism in experimentally induced cardiac failure. Circulation Res. 10: 321, 1962. GEBTLER, M. M.: Differences in efficiency of energy transfer in mitochondrial systems derived from normal and failing hearts. Proc. Soc. Exptl. Biol. Med. 106: 109, 1961. FLECKENSTEIN, A.: Die Bedeutung der energiereichen Phosphate fur Kontraktilitat und Tonus des Myokards. Verhandl. Deut. Ges. Inn. Med. 70: 81, 1964. FURCHGOTT, R. F., AND LEE, K. S.: High energy phosphates and the force of contraction of cardiac muscle. Circulation 24: 416, 1961. FEINSTEEN, M. B.: Effects of experimental congestive heart failure, ouabain, and asphyxia on the high-energy phosphate and creatine content of the guinea pig heart. Circulation Res. 10: 333, 1962. 8. Fox, A. C., WIKI.ER, N. S., AND REED, G. E.: High energy phosphate compounds in the myocardium during experimental congestive heart failure: Purine and pyrimidine nucleotides, creatine, and creatine phosphate in normal and in failing hearts. J. Clin. Invest. 44: 202, 1965. 9. FURCHGOTT, R. F., AND DEGUBAREFF, T.: High energy phosphate content of cardiac muscle under various experimental conditions which alter contractile strength. J. Pharmacol. Exptl. Therap. 124: 203, 1958. 10. OLSON, R. E.: Myocardial metabolism in congestive heart failure. J. Chronic Diseases 9: 442, 1959. 11. MLNTON, P. R., ZOLL, P. M., AND NORMAN, L. R.: Levels of phosphate compounds in experimental cardiac hypertrophy. Circulation Res. 8: 924, 1960. 12. BUCKLEY, N. M., AND TSUBOT, K. K.: Cardiac nucleotides and derivatives in acute and chronic ventricular failure of the dog heart. Circulation Res. 9: 618, 1961. 13. BING, R. J.: Cardiac metabolism. Physiol. Rev. 45: 171, 1965. 14. References WOLLENBERGER, A . , KLEITKE, B . , AND R A A B E , G . : WOLLENBEHGER, A., KRAUSE, E . G., AND W A H L E R , B. E.: Orthophosphatund Phosphokreatingehalt des Herzmuskels. Naturwissenschaften 45: 294, 1958. CircuUsio* Rvurck, Vol. XXI, Septtmbf 1967 MYOCARDIAL ENERGY STORES IN HEART FAILURE 373 Kaplan, New York, Academic Press, vol. 3, p. 871, 1957. 15. POOL, P. E., COVELL, J. W., CHIDSEY, C. A., AND BRAUNWALD, E.: Myocardial high energy phosphate stores in acutely induced hypoxic heart failure. Circulation Res. 19: 221, 1966. 24. A New Approach. Brooklyn, The Free Press of Glencoe, Inc., 1956, p. 420. 16. FUHCHCOTT, R. F., AND DEGUBAREFF, T.: Deter- mination of inorganic phosphate and creatine phosphate in tissue extracts. J. Biol. Chem. 223: 377, 1956. 17. 25. 28. ture extraction of small samples of tissue. Chemist-Analyst. 56: 38, 1967. Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circulation Res. 21: 341, 1967. 20. 27. 28. tine. J. Biol. Chem. 81: 629, 1929. 29. ENNOR, A. H.: Determination and preparation of N-phosphates of biological origin. 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Myocardial High Energy Phosphate Stores in Cardiac Hypertrophy and Heart Failure PETER E. POOL, JAMES F. SPANN, Jr., ROBERT A. BUCCINO, EDMUND H. SONNENBLICK, EUGENE BRAUNWALD and Shirley C. Seogren Downloaded from http://circres.ahajournals.org/ by guest on June 12, 2017 Circ Res. 1967;21:365-374 doi: 10.1161/01.RES.21.3.365 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1967 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/21/3/365 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. 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