Rationally engineered Troponin C modulates in vivo cardiac function and performance in health and disease
Vikram ShettigarBo ZhangSean C. LittleHussam E. SalhiBrian J. HansenNing LiJianchao ZhangSteve RoofHsiang‐Ting HoLucia BrunelloJessica K. LerchNoah WeislederVadim V. FedorovFederica AccorneroJill A. Rafael‐FortneySándor GyörkePaul M.L. JanssenBrandon J. BiesiadeckiMark T. ZioloJonathan P. Davis
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Abstract Treatment for heart disease, the leading cause of death in the world, has progressed little for several decades. Here we develop a protein engineering approach to directly tune in vivo cardiac contractility by tailoring the ability of the heart to respond to the Ca 2+ signal. Promisingly, our smartly formulated Ca 2+ -sensitizing TnC (L48Q) enhances heart function without any adverse effects that are commonly observed with positive inotropes. In a myocardial infarction (MI) model of heart failure, expression of TnC L48Q before the MI preserves cardiac function and performance. Moreover, expression of TnC L48Q after the MI therapeutically enhances cardiac function and performance, without compromising survival. We demonstrate engineering TnC can specifically and precisely modulate cardiac contractility that when combined with gene therapy can be employed as a therapeutic strategy for heart disease.Keywords:
Contractility
Amrinone, a bipyridine compound, has been shown to exert a positive inotropic effect on the heart, without producing cardiac arrhythmias. Because of preliminary observations suggesting that the actions of amrinone might change significantly with growth and development, we studied its effects on the contractility and electrophysiology of isolated cardiac muscle of 0- to 96-day-old beagles and Purkinje fibers of 5-year-old beagles. Amrinone's effects on ventricular muscle contractility were age-related. A significant decrease in contractility of right ventricular trabeculae and papillary muscles (not associated with changes in action potential characteristics) was observed in the 0- to 3-day newborn, whereas, by day 4-10, amrinone increased contractility. The magnitude of the increase became greater through day 96 of life. The negative inotropic effect of amrinone is unassociated with changes in the action potential plateau, suggesting that the slow inward current is not involved in this mechanism.
Amrinone
Contractility
Cardiac muscle
Purkinje fibers
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Contractility
DIGITALIS GLYCOSIDES
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BACKGROUND Most positive inotropic agents increase cardiac contractility by increasing the amount of Ca2+ cycled with each beat. The additional amount of oxygen that is consumed by the heart to cycle this additional Ca2+ is believed to reduce myocardial efficiency. On the other hand, it has been suggested that the agent EMD-53998 increases the Ca2+ sensitivity of the contractile proteins without affecting the intracellular Ca2+ transient in cardiac muscle. Therefore, application of this agent may increase cardiac contractility without decreasing myocardial efficiency. The purpose of the present study was to test this hypothesis. METHODS AND RESULTS We measured myocardial oxygen consumption (MVO2) in six isolated, isovolumically beating blood-perfused canine hearts. The hearts were paced at 120 beats per minute. Contractility was varied in each heart by infusion of either CaCl2 or EMD-53998. With infusion of either agent, MVO2 was a linearly proportional function of contractility. No significant difference between CaCl2 and EMD-53998 could be detected in the interrelation between contractility and MVO2. CONCLUSIONS We conclude that the "calcium-sensitizing agent" EMD-53998 is a potent positive inotropic agent in the isolated, blood-perfused canine heart. However, EMD-53998 does not provide an energetic advantage over currently used positive inotropic agents.
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Cardiac muscle
Cardiac cycle
Calcium in biology
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The influence of the substitution of extracellular Ca by Sr on contractility of papillary muscles of the cat and isolated hearts of the rat and the frog was studied. This substitution resulted in a positive inotropic effect on the frog heart and on the papillary muscle. From the changes observed in the duration of the contraction phenomena, in the rate of tension development and in the force-velocity relationship in the papillary muscle, this positive inotropic effect can be attributed to a prolongation of the active state which offsets a decreased degree of activation. In a Sr containing medium the interaction of frequency with contractility persists but the tension developed at infraoptimal frequencies is higher and the optimal frequency is lower than in a normal medium.
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Cardiac muscle
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Atrium (architecture)
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The effect of the polyfunctional macroheterocycles on the rhythmic and contractile activity of the rat myocardium was found to depend on their concentration. A two-phasic effect upon contractility of the papillary muscles was revealed: a short-term (up to 20 sec) positive inotropic effect followed by a stable depression. The most active drug of this class, dicyclohexano-18-crown-6, prevented the positive inotropic action of classic stimulants (catecholamines and strophantin) upon the contractile function of the heart.
Contractility
Papillary muscle
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Amrinone, a bipyridine compound, has been shown to exert a positive inotropic effect on the heart, without producing cardiac arrhythmias. Because of preliminary observations suggesting that the actions of amrinone might change significantly with growth and development, we studied its effects on the contractility and electrophysiology of isolated cardiac muscle of 0- to 96-day-old beagles and Purkinje fibers of 5-year-old beagles. Amrinone's effects on ventricular muscle contractility were age-related. A significant decrease in contractility of right ventricular trabeculae and papillary muscles (not associated with changes in action potential characteristics) was observed in the 0- to 3-day newborn, whereas, by day 4-10, amrinone increased contractility. The magnitude of the increase became greater through day 96 of life. The negative inotropic effect of amrinone is unassociated with changes in the action potential plateau, suggesting that the slow inward current is not involved in this mechanism.
Amrinone
Contractility
Cardiac muscle
Purkinje fibers
Papillary muscle
Cite
Citations (29)