This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Katz, A. M. Articles by Lorell, B. H. Search for Related Content PubMed PubMed Citation Articles by Katz, A. M. Articles by Lorell, B. H. Related Collections Contractile function Biochemistry and metabolism Calcium cycling/excitation-contraction coupling Cell signalling/signal transduction Heart failure - basic studies

(Circulation. 2000;102:IV-69.)
© 2000 American Heart Association, Inc.

Special Anniversary Issue

Regulation of Cardiac Contraction and Relaxation

Arnold M. Katz, MD; Beverly H. Lorell, MD

From the Cardiology Division (A.M.K.), Department of Medicine, University of Connecticut, Farmington, and the Cardiovascular Division (B.H.L.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass.

Correspondence to Arnold M. Katz, MD, 1592 New Boston Rd, PO Box 1048, Norwich, VT 05055-1048.

Key Words: heart • contractility • inotropy • relaxation • lusitropy • calcium • heart failure

Fifty years ago, end-diastolic volume (Starling’s law of the heart) was generally believed to be the major determinant of cardiac performance. Although length-independent changes in the work of the heart had been observed by many investigators, including Starling, the significance of changing myocardial contractility was not appreciated in 1950, when Circulation was first published. Three articles published that year illustrate this lack of understanding. The first, which described patients with cor pulmonale, noted that digitalis increased the output of the failing right ventricle while right-sided filling pressures were decreased.¹ Although cardiac glycosides were concluded to improve the "function of the failing ventricle," a diagram in this article shows the failing heart operating on the descending limb of a Starling curve, with digitalis bringing the heart back to the apex of this curve. A second article examined digitalis toxicity in patients with heart failure and, citing work on isolated cardiac muscle published in the 1930s, concluded that "increased cardiac output following digitalis administration ... is presumably largely due to an enhanced contractility."² The third article described reflexes that "depress the strength of cardiac contraction," and concluded that autonomic stimulation could "modify the manifestations of Starling’s Law."³ However, because there was no foundation of knowledge that could explain "enhanced contractility," these observations could not be reconciled with the dominant view that end-diastolic volume is the key determinant of cardiac work.

Discovery of the Interplay Between Length-Dependent Changes in Cardiac Function (Starling’s "Law of the Heart") and Changing Myocardial Contractility: The "Family of Starling Curves"

The interplay between regulation by changing end-diastolic volume and changing contractility was clarified by Sarnoff,⁴ who in 1955 described the "family of Starling curves" (). Although this demonstrated that length-independent changes in the contractile properties of cardiac muscle play an important role in regulating the work of the heart, almost 10 years were to pass before these changes, which Sarnoff called myocardial contractility, were explained by discoveries in biochemistry and biophysics.

Discoveries in Skeletal Muscle: The Sliding Filament Hypothesis and Role of Calcium

In 1953, H.E. Huxley and Jean Hanson, using x-ray diffraction⁵ and electron microscopic⁶ data, showed that the length of the macromolecules responsible for muscular contraction does not change when muscle shortens. This was a heretical view, as theories dating back to the 19th century had assumed that muscular contraction depends on the folding of asymmetrical molecules. These new observations indicated instead that muscle shortens and generates tension when myofilaments slide by one another and that the contractile process depends on interactions between cross-bridges made up of the heads of myosin in the thick filaments and actin in the thin filaments. Extension of these studies to cardiac muscle⁷ led to the discovery that Starling’s law is not due primarily to changes in the overlap between the thick and thin filaments but instead occurs because changing sarcomere length modifies the intensity of excitation-contraction coupling.⁸ The key to understanding contractility came in the early 1960s, when calcium was found to be the physiological activator of the contractile proteins in skeletal muscle,^{9 10} and an internal membrane system called the sarcoplasmic reticulum (SR) was shown to be the major source of activator calcium.^{11 12}

At the same time that calcium was discovered to mediate excitation-contraction coupling in skeletal muscle, efforts to understand myocardial contractility were moving in a different direction, toward the view that potassium is the key regulator. Evidence that many positive inotropic interventions are accompanied by increased potassium efflux from the myocardium,¹³ along with earlier observations that high potassium concentrations inhibit the interactions between actin and myosin in vitro, were interpreted as evidence that potassium efflux plays a central role in increasing myocardial contractility.¹⁴ This view found support in a generally overlooked observation of Ringer, who of course is remembered today for his discovery that extracellular calcium is essential for cardiac contraction. However, Ringer had also found that increasing extracellular potassium weakens contraction of the frog heart,¹⁵ a phenomenon that is now explained by effects of this alkali metal ion on excitability rather than contractility.

Regulation of Cardiac Contraction and Relaxation by Calcium: Functional Signaling

Troponin as the Calcium Receptor for Excitation-Contraction Coupling
That calcium and not potassium is the major determinant of myocardial contractility became clear when Ebashi and Kodama¹⁶ described troponin, and regulatory proteins in the thin filament were found to be essential for micromolar calcium concentrations to activate the contractile proteins of skeletal muscle in vitro.¹⁷ In 1966, discovery of a similar calcium-sensitive regulatory mechanism in the heart¹⁸ opened a new area of discovery regarding cardiac regulation.

SR as the Source of Calcium for Excitation-Contraction Coupling
The pioneering work that had defined the role of the SR in skeletal muscle led to the next major advance in understanding myocardial contractility, which occurred in the late 1960s, when the cardiac SR was shown to have both the affinity and capacity to remove all of the calcium bound to troponin.^{19 20} The cardiac SR calcium pump was purified in 1970,²¹ and its structure was published in 1985.²² A related plasma membrane calcium pump ATPase that transports calcium out of the cell was described in the early 1980s.²³ Characterization of the intracellular channel that releases calcium from these internal membranes, often called the ryanodine receptor, closed a major gap in understanding the role of the SR in excitation-contraction coupling.²⁴

Recognition that the contractile proteins are activated by downhill calcium fluxes and that relaxation requires the active, uphill transport of calcium into the SR and out of the cell answered a once "classic" question: "Does contraction or relaxation require energy?" The answer, of course, is both. The role of energy starvation in the living heart was clarified with the discovery that the normal cytosolic ATP concentration is 5 to 10 mmol/L, whereas the substrate-binding sites of most ATP-hydrolyzing systems are saturated at ATP concentrations of <1 µmol/L; these findings made it very unlikely that, except in the dying heart, ATP concentrations can fall to levels below those needed to saturate known ATPase enzymes. Observations that high ATP concentrations exert allosteric effects that accelerate ion pumps, ion exchangers, and passive ion fluxes through membrane channels suggested that reduction in these regulatory effects can reduce inotropy and lusitropy in the energy-starved heart. An even more important consequence was discovered to be a decrease in the energy made available by hydrolysis of the terminal phosphate of ATP, the free energy of ATP hydrolysis, or -G.²⁵ Even a slight fall in the ATP-to-ADP ratio, which in the energy-starved heart is due mainly to an increase in ADP concentration, can slow both the calcium pump of the SR and cross-bridge cycling.²⁶

The Sodium/Calcium Exchanger, Sodium Pump, and Mechanism of Action of Digitalis
Despite Ringer’s early observation that cardiac contraction depends on extracellular calcium, in 1950 virtually nothing was known of the role of calcium in regulating myocardial contractility. A puzzling observation made in 1948 that contractility in the frog heart is proportional to the ratio between extracellular sodium and calcium²⁷ led to the discovery of the sodium/calcium exchanger, an antiport that can carry either of these ions in either direction across the plasma membrane.²⁸ The structure of this exchanger was published in 1990.²⁹

Competition between sodium and calcium for transport by the sodium/calcium exchanger made it possible to explain the inotropic effect of the cardiac glycosides. Although early reports described direct interactions of the cardiac glycosides with the contractile proteins, and after the discovery of the role of the SR with the calcium pump, these were never convincing. Instead, the mechanism became clear when cardiac glycosides were found to inhibit the sodium pump.^{30 31} In 1964, recognition that increased cytosolic sodium inhibits calcium efflux from the myocardium via the sodium/calcium exchanger explained how sodium pump inhibition could increase myocardial contractility.³² Many years were to pass, however, before this explanation for one of the oldest problems in cardiology came to be generally accepted.

Calcium Influx, Slow Inward Current, and Calcium-Triggered Calcium Release
The function of extracellular calcium in regulating myocardial contractility was discovered in the early 1960s, when stimulation was found to increase calcium influx across the plasma membrane.^{33 34} At that time, however, a physiological role for this calcium influx seemed doubtful, because action potentials in nerve and skeletal muscle could be explained almost entirely by sodium and potassium fluxes across the plasma membrane and because skeletal muscle can respond to electrical stimulation when extracellular calcium is very low. It was not until 1968 that myocardial contractility was found to be proportional to the magnitude of an inward calcium current across the plasma membrane³⁵ : this depolarizing calcium current was called the "slow inward current" because it activates and inactivates more slowly than the larger, sodium current responsible for the action potential upstroke. Increased calcium influx explains the inotropic effect of increased heart rate (the positive staircase described by Bowditch at the end of the 19th century) and, as described below, contributes to the inotropic effect of ß-adrenergic stimulation.

The role of calcium entry in cardiac excitation-contraction coupling was subsequently explained by the finding that calcium release from the cardiac SR, unlike that of skeletal muscle, depends on a small calcium influx across the plasma membrane in a process called "calcium-triggered calcium release".³⁶ Calcium release from the cardiac SR, which causes localized "calcium sparks" that can be visualized when cells are injected with calcium-sensitive dyes,^{37 38} is a critical determinant of myocardial contractility.

Modification of Myofilament Responsiveness to Calcium and the Role of pH
Mines, at the beginning of the 20th century, found that acidosis reduces the strength of cardiac contraction. The mechanism was identified when protons were discovered to reduce the calcium sensitivity of purified contractile protein preparations³⁹ and skinned cardiac fibers.⁴⁰ Changes in the myofibrillar responsiveness to calcium caused by ß-adrenergic agonists (see below) and -adrenergic agonists⁴¹ were subsequently found to modify both inotropy and lusitropy.

These discoveries were followed by observations that the inotropic responses of mammalian cardiac cells to angiotensin II and endothelin-1, as well as to -adrenergic agonists, occur when protein kinase C causes intracellular alkalization. The resulting changes in intracellular pH are regulated predominantly by a Na⁺/H⁺ exchanger,⁴² which, along with the related Na⁺/HCO₃^- symport and the sodium-dependent HCO₃/Cl^- antiport, allows changing intracellular pH to regulate contractility in both normal and failing hearts.⁴³

Norepinephrine, cAMP, Protein Kinase A, and Phospholamban
Efforts to explain the heart’s response to sympathetic stimulation began with a search for direct interactions of catecholamines with the contractile proteins and the SR. As was the case for the cardiac glycosides, positive results were published, but most could not be repeated. Discovery of the role of cAMP as an intracellular second messenger⁴⁴ and the ability of cAMP-dependent protein kinases (protein kinase A) to catalyze phosphorylations that mediate responses to ß-adrenergic agonists^{45 46} stimulated 4 groups to test the hypothesis that norepinephrine causes cAMP-activated phosphorylation of the SR.^{47 48 49 50} This led to the discovery of phospholamban, a regulatory protein that in its dephospho form inhibits the SR calcium ATPase.⁵¹ The ability of phospholamban phosphorylation to stimulate calcium uptake by the cardiac SR was immediately recognized to provide an explanation for the lusitropic effect of sympathetic activation. Although phospholamban phosphorylation had been suggested in 1973 to increase contractility by enhancing calcium loading of the SR within the myocardium,⁵² this hypothesis was not confirmed until the 1990s, when studies were carried out in transgenic mice that lack⁵³ and overexpress⁵⁴ this regulatory protein.

The lusitropic effect of ß-adrenergic stimulation was subsequently found to be mediated also when protein kinase A–catalyzed phosphorylation of troponin I desensitizes the contractile proteins to calcium.^{55 56} This effect not only facilitates relaxation but also increases the calcium requirement for contraction. However, the inotropic effect of ß-adrenergic stimulation predominates because of another important response to sympathetic stimulation, an increase in the slow inward (calcium) current⁵⁷ that overcomes the decreased calcium sensitivity of troponin. Together, these effects increase contractility and accelerate relaxation so as to provide an integrated response that is essential in allowing the inotropically stimulated heart to fill during sympathetic stimulation, when increased heart rate shortens diastole.

Regulation of Contraction and Relaxation by Molecular Changes and Modification of Phenotype: Transcriptional Signaling

Fifty years ago, the failing heart was generally assumed to operate on the descending limb of the Starling curve (see Reference 1¹ ). Sarnoff’s demonstration that negative inotropic interventions shift the heart to a depressed Starling curve,⁴ along with the recognition that the heart cannot operate at a steady state on the descending limb,⁵⁸ suggested instead that contractility is depressed in diseased hearts. Confirmation of this hypothesis in 1967⁵⁹ had a major impact on concepts regarding heart failure, which came to be viewed largely as a pump disorder caused by depressed myocardial contractility. Although relaxation and filling abnormalities were subsequently recognized in failing hearts,⁶⁰ a new paradigm, that of transcriptional regulation, has now emerged as the major cause of the chronic inotropic and lusitropic abnormalities in heart disease.

Changes in contractility and relaxation, such as those caused by altered pH, digitalis, and ß-adrenergic stimulation, can be viewed as functional responses that develop rapidly, generally over a few seconds or minutes. These responses, which are effected by mechanisms like altered calcium fluxes and posttranslational phosphorylations, differ fundamentally from transcriptional (proliferative) responses that evolve over days, months, and often years. The latter are caused by activation of transcription factors that regulate gene expression, protein synthesis, cell growth and division, and programmed cell death (apoptosis). Because adult cardiac myocytes have little or no ability to divide, transcriptionally mediated changes increase cell size (hypertrophy) and modify molecular composition. The resulting changes in organ structure and function have profound effects on both ejection and filling that are central to the long-term adjustments of pump function when adult hearts are subjected to chronic stress.

The first evidence that transcriptional regulation modifies myocardial contractility was published in 1962, when ATPase activity was found to be depressed in myofibrils isolated from failing human hearts.⁶¹ This discovery, and subsequent observations that myosin ATPase activity is altered by hyperthyroidism,⁶² marked a paradigm shift, as it demonstrated that cardiac performance can be regulated by changes in the composition of the heart. It soon became clear that these transcriptional responses are at least as important as the functional responses that alter the behavior of preexisting structures in the heart.

Transcriptional responses play an important role in chronically overloaded hearts, where they not only promote cell growth and apoptosis but also reduce contractility and impair relaxation. Many of these changes, which are most marked in pressure overload, involve enzymes of energy metabolism, myofilaments, the cytoskeleton, membrane channels, ion exchangers and pumps, and proteins that mediate cell signaling.

The initial finding of a fall in myofibrillar ATPase activity in failing hearts (see above) was subsequently shown to be due to an isoform shift in which the adult, high-ATPase cardiac myosin -heavy chain is replaced with the lower-activity fetal ß-heavy chain.⁶³ More recent work has identified additional shifts to fetal isoforms, including some that alter the calcium sensitivity of the contractile proteins. A second type of transcriptional response, which slows relaxation, is not caused by an isoform shift but instead is due to reduced expression of the SR calcium pump ATPase.⁶⁴ This also represents a reversion to the fetal phenotype, as contraction and relaxation in embryonic hearts depend mainly on calcium fluxes between the cytosol and extracellular fluid, rather than between the cytosol and internal stores within the SR.

The plasticity of transcriptional regulation of myocardial contractility was demonstrated in the early 1970s, when physical training was found to increase both actomyosin ATPase activity⁶⁵ and calcium uptake by the SR.⁶⁶ These responses, which increase contractility and accelerate relaxation, represent enhanced expression of the adult phenotype and are opposite to the changes seen in chronically overloaded hearts.

The recent discovery that the sodium/calcium exchanger, which transports calcium out of the cell across the plasma membrane, is upregulated in failing hearts^{67 68} represents another example of reversion to the fetal phenotype; in this case, a greater reliance on calcium fluxes across the plasma membrane than on calcium fluxes into and out of the SR. Increased activity of the sodium/calcium exchanger helps relax the heart, but by reducing calcium loading of the SR, also decreases contractility.⁶⁹

Conclusions

The initial clinical promise of therapy based on the physiologically and biologically based discoveries regarding cardiac contraction and relaxation described in this article has not, unfortunately, been fulfilled. Although alleviation of the obvious hemodynamic consequences of depressed contractility and impaired relaxation is of short-term clinical benefit, efforts to "correct" maladaptive functional signaling often have adverse long-term effects. For example, powerful inotropic agents, such as phosphodiesterase inhibitors, transiently improve hemodynamics but shorten survival.^{70 71} More surprising, in the context of the history reviewed in this article, is evidence that ß-adrenergic blockers, despite their initial negative inotropic (functional) effects, improve long-term prognosis^{72 73 74 75} and slow the progressive dilatation of the failing heart,^{76 77} called remodeling, that results from transcriptional signaling. The ability of converting-enzyme inhibitors, which also prolong survival in heart failure,⁷⁸ to inhibit remodeling^{77 79} highlights the importance of maladaptive transcriptional signaling in this clinical syndrome.

Fifty years after publication of the first volumes of Circulation, therefore, explanations of heart disease appear once again to require a new paradigm. Much as the physiological explanations that dominated cardiology were being superseded by biochemical and biophysical explanations in the 1950s, emphasis today is moving from functional to transcriptional regulation. Clinical trials suggest that the current paradigm shift, which is changing efforts to treat heart failure from correcting functional abnormalities in contractility and relaxation to modifying inappropriate transcriptional signaling, will prove to be of considerable practical benefit.

View this table: [in this window] [in a new window]   Table 1. Major Milestones in the Growth of Knowledge of the Regulation of Cardiac Contraction and Relaxation: 1950–2000

References

1. Ferrer MI, Harvey RM, Cathcart RT, et al. Some effects of digoxin upon the heart and circulation in man: digoxin in chronic cor pulmonale. Circulation. 1950;1:161–186.

2. Batterman RL, Gutner LB. Increasing congestive heart failure: a manifestation of digitalis toxicity. Circulation. 1950;1:1052–1059.

3. Peterson LH. Some characteristics of certain reflexes which modify the circulation in man. Circulation. 1950;2:351–362.

4. Sarnoff SJ. Myocardial contractility as described by ventricle function curves; observations on Starling’s Law of the Heart. Physiol Rev. 1955;35:107–122.

5. Huxley HE. X-ray analysis and the problem of muscle. Proc R Soc B. 1953;141:59–66.

6. Hanson J, Huxley HE. Structural basis of the cross-striations in muscle. Nature. 1953;172:530–532.

7. Huxley HE. The contractile structure of cardiac and skeletal muscle. Circulation. 1961;24:328–335.

8. Fabiato A, Fabiato F. Dependence of the contractile activation of skinned cardiac cells on the sarcomere length. Nature. 1975;256:54–56.[Medline]

9. Weber A, Winicur S. The role of calcium in the superprecipitation of actomyosin. J Biol Chem. 1961;236:3198–3202.

10. Ebashi S. Third component participating in the superprecipitation of "natural actomyosin." Nature. 1963;200:1010–1012.

11. Hasselbach W, Makinose M. Die Calciumpumpe der Erschlaffungsgrane des Muskels und ihre Abhängigheit von der ATP-Spaltung. Biochem Z. 1961;333:518–528.

12. Ebashi S, Lipman F. Adenosine triphosphate-linked accumulation concentration of calcium ions in a particulate fraction of rabbit muscle. J Cell Biol. 1962;14:389–400.

13. Hajdu S. Mechanism of staircase and contracture in ventricular muscle. Am J Physiol. 1953;174:371–380.

14. Sarnoff SJ, Gilmore JP, Mitchell JH, et al. Potassium changes in the heart during homeometric autoregulation and acetylstrophanthidin. Am J Med. 1963;34:440–451.

15. Ringer S. A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J Physiol (Lond). 1883;4:29–47.

16. Ebashi S, Kodama A. A new protein factor promoting aggregation of tropomyosin. J Biochem (Tokyo). 1965;58:107–108.[Medline]

17. Katz AM. Purification and properties of a tropomyosin-containing protein fraction that sensitizes reconstituted actomyosin to calcium-binding agents. J Biol Chem. 1966;241:1522–1529.[Medline]

18. Katz AM, Repke DI, Cohen B. Control of the activity of highly purified cardiac actomyosin by Ca⁺⁺ Na⁺ and K⁺. Circ Res. 1966;19:1062–1070.[Medline]

19. Katz AM, Repke DI. Quantitative aspects of dog cardiac microsomal calcium binding and calcium uptake. Circ Res. 1967;21:153–162.[Medline]

20. Harigaya S, Schwartz A. Rate of calcium binding and uptake in normal animal and failing human cardiac muscle: membrane vesicles (relaxing system) and mitochondria. Circ Res. 1969;25:781–794.[Medline]

21. MacLennan DH. Purification and properties of an adenosine triphosphatase from sarcoplasmic reticulum. J Biol Chem. 1970;245:4508–4518.[Medline]

22. MacLennan DH, Brandl CL, Korczak B, et al. Amino-acid sequence of a Ca²⁺ + Mg²⁺-dependent ATPase from rabbit muscle sarcoplasmic reticulum, deduced from its complementary DNA sequence. Nature. 1985;316:696–700.[Medline]

23. Caroni P, Carafoli E. An ATP-dependent Ca²⁺-pumping system in dog heart sarcolemma. Nature. 1980;283:765–767.[Medline]

24. Inui M, Saito A, Fleischer S. Isolation of the ryanodine receptor from cardiac sarcoplasmic reticulum and identity with the feet structures. J Biol Chem. 1987;262:15637–15642.[Abstract]

25. Kammermeier H, Schmidt P, Jüngling E. Free energy change of ATP-hydrolysis: a causal factor of early hypoxic failure of the myocardium? J Mol Cell Cardiol. 1982;14:267–277.[Medline]

26. Tian R, Ingwall JS. Energetic basis for reduced contractile reserve in isolated rat hearts. Am J Physiol. 1996;270:H1207–H1216.[Medline]

27. Wilbrandt W, Koller H. Die Calcium-Wirkung am Froschherzen als Funktion des Ionengleichgewichts zwischen Zellmembran und Umgebung. Helv Physiol Acta. 1948;6:208–221.

28. Lüttgau HC, Niedergerke R. The antagonism between Ca and Na ions on the frog’s heart. J Physiol (Lond). 1958;143:486–505.

29. Nicoll DA, Longoni S, Philipson KD. Molecular cloning and functional expression of the cardiac sarcolemmal Na⁺-Ca²⁺ exchanger. Science. 1990;250:469–471.

30. Schätzmann HJ. Herzglykoside als hemmstoffe für den aktiven Kalium- und Natriumtransport durch die Erythrocytenmembran. Helv Physiol Acta. 1953;11:346–354.

31. Glynn IM. The action of cardiac glycosides on sodium and potassium movements in human red cells. J Physiol (Lond). 1957;136:148.

32. Repke K. Über den biochemischen Wirkungsmodus von Digitalis. Klin Wochenschr. 1964;41:156–165.

33. Winegrad S, Shanes AM. Calcium flux and contractility in guinea pig atria. J Gen Physiol. 1962;45:371–394.

34. Langer GA, Brady AJ. Calcium flux in the mammalian ventricular myocardium. J Gen Physiol. 1963;46:703–719.

35. Reuter H, Scholz H. Über den Einfluss der extracellulären Ca-Konzentration auf Membranpotential und Kontraktion isolierter Herzpräparate bei graduierter Depolarisation. Pflügers Arch. 1968;300:87–107.

36. Fabiato A. Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol. 1983;245:C1–C14.[Medline]

37. Cheng H, Lederer WJ, Cannell MB. Calcium sparks elementary events underlying excitation-contraction coupling in heart muscle. Science. 1993;262:740–743.[Medline]

38. Wier WG, Egan TM, López-López JR, et al. Local control of excitation-contraction coupling in rat heart cells. J Physiol (Lond). 1994;474:463–471.[Medline]

39. Schädler MH. Porportionale Aktivierung van ATPase-Aktivität und Kontraktionspannung durch Caliumionen in isolierten contraktilen Strukturen verschiedener Muskelarten. Pflügers Arch Ges Physiol. 1967;296:70–90.

40. Fabiato A, Fabiato F. Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiac and skeletal muscles. J Physiol (Lond). 1978;276:233–255.[Medline]

41. Blinks JR, Endoh M. Modification of myofibrillar responsiveness to Ca⁺⁺ as an inotropic mechanism. Circulation. 1986;73(suppl III):III-85–III-98.

42. Matsui H, Barry WH, Spitzer KW. Angiotensin II stimulates sodium-hydrogen exchange in adult rabbit ventricular myocytes. Circ Res. 1995;29:215–221.

43. Ito N, Kagaya Y, Weinberg EO, et al. Endothelin and angiotensin II stimulation of Na⁺-H⁺ exchange is impaired in cardiac hypertrophy. J Clin Invest. 1997;99:125–135.[Abstract/Full Text]

44. Sutherland EW, Robison GA, Butcher RW. Some aspects of the biological role of adenosine 3',5'-monophosphate (cyclic AMP). Circulation. 1968;37:279–306.

45. Walsh DA, Perkins JP, Krebs EG. An adenosine 3',5'-monophosphate-dependent protein kinase from rabbit skeletal muscle. J Biol Chem. 1968;243:3763–3765.[Medline]

46. Miyamoto E, Kuo JF, Greengard P. Adenosine 3',5'-monophosphate-dependent protein kinase from brain. Science. 1969;165:64–65.

47. Kirchberger MA, Tada M, Repke DI, et al. Cyclic adenosine 3',5'-monophosphate dependent protein kinase stimulation of calcium uptake by canine cardiac microsomes. J Mol Cell Cardiol. 1972;4:673–680.[Medline]

48. Wollenberger A. Cyclic nucleotides and the regulation of heart beat. Abstracts From the Fifth International Congress of Pharmacology, July 23–28, 1972. San Francisco, CA: Union of Pharmacol. 1972:231–233.

49. LaRaia PJ, Morkin E. Adenosine 3',5'-monophosphate dependent membrane phosphorylation: a possible mechanism for the control of microsomal calcium transport in heart muscle. Circ Res. 1974;35:298–306.

50. Wray HL, Gray RR, Olsson RA. Cyclic adenosine 3‘,5'-monophosphate-stimulated protein kinase and a substrate associated with cardiac sarcoplasmic reticulum. J Biol Chem. 1973;248:1496–1498.[Medline]

51. Tada M, Kirchberger MA, Katz AM. Phosphorylation of a 22,000-dalton component of the cardiac sarcoplasmic reticulum by adenosine 3',5' -monophosphate dependent protein kinase. J Biol Chem. 1975;250:2640–2647.[Medline]

52. Katz AM, Kirchberger MA, Tada M, et al. Epinephrine-induced enhancement of myocardial contractility: possible mediation by ß-receptor: adenylate cyclase: adenosine 3',5'-monophosphate-dependent protein kinase: calcium transport system located on the sarcoplasmic reticulum. J Clin Invest. 1973;52:46a. Abstract.

53. Luo W, Grupp IL, Harrer J, et al. Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of ß-agonist stimulation. Circ Res. 1994;75:401–409.[Abstract]

54. Chu G, Dorn GW II, Luo W, et al. Monomeric phospholamban overexpression in transgenic mouse hearts. Circ Res. 1997;81:485–492.[Abstract/Full Text]

55. Ray KP, England PJ. Phosphorylation of the inhibitory subunit of troponin and its effect on the calcium-dependence of cardiac myofibril ATPase. FEBS Lett. 1976;70:11–16.[Medline]

56. Bailin G. Phosphorylation of a bovine cardiac actin complex. Am J Physiol. 1979;236:C41–C46.[Medline]

57. Reuter H. Localization of ß-adrenergic receptors, and effects of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle. J Physiol (Lond). 1976;242:429–451.

58. Katz AM. The descending limb of the Starling Curve and the failing heart. Circulation. 1965;32:871–875.[Medline]

59. Spann JF Jr, Buccino RA, Sonnenblick EH, et al. Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circ Res. 1967;21:341–354.[Medline]

60. Grossman W, McLaurin LP, Rolett EL. Alteration in left ventricular relaxation and diastolic compliance in congestive cardiomyopathy. Cardiovasc Res. 1979;13:514–522.[Medline]

61. Alpert NR, Gordon MS. Myofibrillar adenosine triphosphatase activity in congestive heart failure. Am J Physiol. 1962;202:940–946.

62. Bannerjee SK, Kabbas EG, Morkin E. Enzymatic properties of the heavy meromyosin subfragment of cardiac myosin from normal and thyrotoxic rabbits. J Biol Chem. 1977;252:6925–6929.[Medline]

63. Lompré AM, Schwartz K, D’Albis A, et al. Myosin isozymes redistribution in chronic heart overloading. Nature. 1979;282:105–107.[Medline]

64. De la Bastie D, Levitsky D, Rappaport L, et al. Function of the sarcoplasmic reticulum and expression of its Ca²⁺ ATPase gene in pressure-overloaded cardiac hypertrophy in the rat. Circ Res. 1990;66:554–564.[Abstract]

65. Bhan AK, Scheuer J. Effects of physical training on cardiac actomyosin adenosine triphosphatase activity. Am J Physiol. 1972;223:1486–1490.[Medline]

66. Penpargkul S, Repke DI, Katz AM, et al. Effect of physical training on calcium transport by rat cardiac sarcoplasmic reticulum. Circ Res. 1977;40:134–138.[Abstract]

67. Studer R, Reinecke H, Bilger J, et al. Gene expression of the cardiac Na⁺-Ca²⁺ exchanger in end-stage human heart failure. Circ Res. 1994;75:443–453.[Abstract]

68. Hasenfuss G, Schillinger W, Lehnart SE, et al. Relationship between Na⁺-Ca²⁺ exchanger protein levels and diastolic function of failing human myocardium. Circulation. 1999;99:641–648.[Abstract/Full Text]

69. Pieske B, Maier LS, Bers DM, et al. Ca²⁺ handling and sarcoplasmic reticulum Ca²⁺ content in isolated failing and nonfailing human myocardium. Circ Res. 1999;85:38–46.[Abstract/Full Text]

70. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med. 1991;325:1468–1475.[Medline]

71. Cohn JN, Goldstein SO, Greenberg BH, et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med. 1998;339:1810–1816.[Medline]

72. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: US Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–1355.[Medline]

73. LeChat P, Packer M, Chalon S, et al. Clinical effects of ß-adrenergic blockade in chronic heart failure. Circulation. 1998;98:1184–1191.[Abstract/Full Text]

74. CIBIS-II Investigators and Committees The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13.[Medline]

75. Merit-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999;353:2001–2007.[Medline]

76. Hall SA, Cigarroa CG, Marcoux L, et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with ß-adrenergic blockade. J Am Coll Cardiol. 1995;25:1154–1161.[Medline]

77. Sabbah HN, Shimoyama H, Kono T, et al. Effect of long-term monotherapy with enalapril, metoprolol, and digoxin on the progression of left ventricular dysfunction and dilatation in dogs with reduced ejection fraction. Circulation. 1994;89:2852–2859.[Abstract]

78. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med. 1987;316:1429–1435.[Medline]

79. Hayashida W, Van Eyll C, Rousseau MF, et al. Regional remodeling and nonuniform changes in diastolic function in patients with left ventricular dysfunction: modification by long-term enalapril treatment. J Am Coll Cardiol. 1993;22:1403–1140.[Medline]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Katz, A. M. Articles by Lorell, B. H. Search for Related Content PubMed PubMed Citation Articles by Katz, A. M. Articles by Lorell, B. H. Related Collections Contractile function Biochemistry and metabolism Calcium cycling/excitation-contraction coupling Cell signalling/signal transduction Heart failure - basic studies