Sparking the Failing Heart
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《新英格兰医药杂志》
Despite advances in the management of congestive heart failure (CHF), most patients with advanced forms die within a year after receiving the diagnosis. Half of all deaths from CHF are caused by ventricular tachycardia, and about 80 percent of patients with symptomatic systolic dysfunction have ventricular tachycardia. Ischemia and myocardial scars are major determinants of the risk of ventricular tachycardia, along with some CHF therapies themselves — for example, inotropic agents such as milrinone and dobutamine. Other available medications include beta-blockers, agents that block the renin–angiotensin–aldosterone pathway, vasodilators, diuretics, and natriuretics. A new study by Wehrens et al.1 points to a different approach: correcting the abnormal handling of calcium by failing myocytes.
In normal myocytes, calcium enters cells through L-type channels, inciting further release of calcium from the sarcoplasmic reticulum through the ryanodine receptor–calcium-release channel (RyR2). The result is actin–myosin cross-bridging and myocyte contraction. The synchronous release of calcium through clusters of RyR2 is termed the "calcium spark," and its magnitude, in part, determines myocardial contractility.
RyR2 activity is highly regulated by the channel-stabilizing protein calstabin2 (also known as FKBP12.6) (Figure 1). During diastole, calstabin2 binds to RyR2 and maintains channel closure. When RyR2 is phosphorylated by cyclic AMP–dependent protein kinase A as a result of beta-adrenergic stimulation, calstabin2 dissociates from RyR2. Consequently, RyR2 is more likely to be open, and its activation is triggered by smaller amounts of calcium. Chronic adrenergic stimulation of cardiac myocytes occurs in failing hearts and in a rare, inherited form of exercise-induced ventricular tachycardia caused by mutations of RyR2.2 Sustained stimulation causes down-regulation of beta-adrenergic receptors and hyperphosphorylation of RyR2 by protein kinase A. Consequently, calstabin2 dissociates from RyR2, and sarcoplasmic calcium leaks into the cytoplasm during diastole (Figure 1). This calcium leak can generate delayed after-depolarizations that may trigger ventricular tachycardia and sudden death. Chronic calcium leakage also depletes the sarcoplasmic reticulum of calcium stores, with a resultant reduction in myocardial contractility.
Figure 1. Calcium Release and Calstabin2.
The transport of calcium ions (Ca2+) in muscle fibers is pivotal to the coordination of muscle contraction and hence to the mechanisms underlying congestive heart failure. In the normal heart, cyclic AMP–mediated activation of protein kinase A in response to adrenergic stimuli causes phosphorylation (P) of the ryanodine channel (RyR2) and dissociation of calstabin2. The result is the release of stored calcium from the sarcoplasmic reticulum through the RyR2 complex. This calcium efflux leads to changes in actin–myosin cross-bridging and myocyte contraction during systole. In the failing heart, RyR2 is not fully bound by calstabin2 due to excess RyR2 phosphorylation. As a result, the RyR2 channels remain partially open during diastole with consequent calcium leakage and depletion of calcium stores. Thus, in response to adrenergic stimuli, less calcium is released through the RyR2 channels, and systolic myocyte contraction is reduced. Wehrens and colleagues1 show that treatment with a small compound, JTV519, stabilizes the binding of calstabin2 to RyR2 and thereby maintains appropriate closure of the RyR2 channel. Calcium leakage is prevented, calcium stores are replenished, and calcium release is enhanced, with a consequent improvement in systolic contraction.
Wehrens et al. showed that pretreatment with a derivative of 1,4-benzothiazepine (JTV519) enhances the binding of calstabin2 to RyR2 and prevents arrhythmias and exercise-induced sudden death in mice with a partial deficiency of calstabin2.1 Mice with a complete deficiency of calstabin2 have exercise-induced arrhythmias and die suddenly on exercising after the receipt of a low, priming dose of epinephrine. When mice with a partial deficiency of calstabin 2, which are asymptomatic at rest, undergo exercise stress testing, ventricular tachycardia or syncope develops, and most die during or shortly after exercise. Ventricular tachycardia could be induced in the mice with a partial deficiency of calstabin2 by administering an infusion of isoproterenol and subjecting them to electrophysiological programmed stimulation with overdrive pacing or with two coupled premature ventricular beats, but not after pretreatment with JTV519. Pretreatment with JTV519 prevented all arrhythmic events and deaths in the mice with a partial deficiency of calstabin2.
JTV519 significantly increases the affinity of calstabin2 for phosphorylated RyR2 (the phosphorylation of RyR2 normally decreases the affinity of RyR2 for calstabin2). Other drugs that increase the binding of calstabin2 to RyR2 and decrease the risk of arrhythmia, such as beta-blockers, do so by reducing the hyperphosphorylation of RyR2 commonly found in hyperadrenergic states and the failing human heart.3,4 Thus, whereas both JTV519 and beta-blockers modify RyR2 activity by enhancing calstabin2 binding, they act through different mechanisms and could act synergistically to improve clinical outcomes.
The study by Wehrens et al. opens a door for the treatment of CHF and the prevention of sudden death. Since it addresses the antiarrhythmic activity of JTV519 only in a genetically engineered calstabin2-knockout model, in which the primary myocardial lesion (calcium leakage) is diastolic and the drug requires intravenous delivery, future studies will need to address the antiarrhythmic activity of calstabin2 stabilizers in ischemic and nonischemic models of systolic dysfunction, in addition to the potency of orally delivered congeners. The idea that calstabin2 stabilizers may help to counter systolic dysfunction is supported by the finding that JTV519 improves hemodynamics in dogs with systolic heart failure induced by sustained, rapid, right ventricular pacing.5
An intriguing question is whether calstabin2 stabilizers can help prevent CHF or whether their efficacy is restricted to active CHF in which the downward spiral of calstabin2 dissociation from RyR2 has already been activated. Just as angiotensin-converting–enzyme inhibitors arose out of basic analyses of neurohormonal signaling mechanisms and revolutionized our approach to CHF, the use of calstabin2 stabilizers to control a mechanism central to the failing heart may someday be an essential weapon in our clinical arsenal.
Source Information
From the Molecular Cardiology Laboratory and Congestive Heart Failure Center, Greenberg Cardiology Division, Department of Medicine, Weill Medical College of Cornell University, New York.
References
Wehrens XH, Lehnart SE, Reiken SR, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 2004;304:292-296.
Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001;103:196-200.
Reiken S, Gaburjakova M, Gaburjakova J, et al. Beta-adrenergic receptor blockers restore cardiac calcium release channel (ryanodine receptor) structure and function in heart failure. Circulation 2001;104:2843-2848.
Marx SO, Reiken S, Hisamatsu Y, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 2000;101:365-376.
Yano M, Kobayashi S, Kohno M, et al. FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. Circulation 2003;107:477-484.(Maryjane A. Farr, M.D., a)
In normal myocytes, calcium enters cells through L-type channels, inciting further release of calcium from the sarcoplasmic reticulum through the ryanodine receptor–calcium-release channel (RyR2). The result is actin–myosin cross-bridging and myocyte contraction. The synchronous release of calcium through clusters of RyR2 is termed the "calcium spark," and its magnitude, in part, determines myocardial contractility.
RyR2 activity is highly regulated by the channel-stabilizing protein calstabin2 (also known as FKBP12.6) (Figure 1). During diastole, calstabin2 binds to RyR2 and maintains channel closure. When RyR2 is phosphorylated by cyclic AMP–dependent protein kinase A as a result of beta-adrenergic stimulation, calstabin2 dissociates from RyR2. Consequently, RyR2 is more likely to be open, and its activation is triggered by smaller amounts of calcium. Chronic adrenergic stimulation of cardiac myocytes occurs in failing hearts and in a rare, inherited form of exercise-induced ventricular tachycardia caused by mutations of RyR2.2 Sustained stimulation causes down-regulation of beta-adrenergic receptors and hyperphosphorylation of RyR2 by protein kinase A. Consequently, calstabin2 dissociates from RyR2, and sarcoplasmic calcium leaks into the cytoplasm during diastole (Figure 1). This calcium leak can generate delayed after-depolarizations that may trigger ventricular tachycardia and sudden death. Chronic calcium leakage also depletes the sarcoplasmic reticulum of calcium stores, with a resultant reduction in myocardial contractility.
Figure 1. Calcium Release and Calstabin2.
The transport of calcium ions (Ca2+) in muscle fibers is pivotal to the coordination of muscle contraction and hence to the mechanisms underlying congestive heart failure. In the normal heart, cyclic AMP–mediated activation of protein kinase A in response to adrenergic stimuli causes phosphorylation (P) of the ryanodine channel (RyR2) and dissociation of calstabin2. The result is the release of stored calcium from the sarcoplasmic reticulum through the RyR2 complex. This calcium efflux leads to changes in actin–myosin cross-bridging and myocyte contraction during systole. In the failing heart, RyR2 is not fully bound by calstabin2 due to excess RyR2 phosphorylation. As a result, the RyR2 channels remain partially open during diastole with consequent calcium leakage and depletion of calcium stores. Thus, in response to adrenergic stimuli, less calcium is released through the RyR2 channels, and systolic myocyte contraction is reduced. Wehrens and colleagues1 show that treatment with a small compound, JTV519, stabilizes the binding of calstabin2 to RyR2 and thereby maintains appropriate closure of the RyR2 channel. Calcium leakage is prevented, calcium stores are replenished, and calcium release is enhanced, with a consequent improvement in systolic contraction.
Wehrens et al. showed that pretreatment with a derivative of 1,4-benzothiazepine (JTV519) enhances the binding of calstabin2 to RyR2 and prevents arrhythmias and exercise-induced sudden death in mice with a partial deficiency of calstabin2.1 Mice with a complete deficiency of calstabin2 have exercise-induced arrhythmias and die suddenly on exercising after the receipt of a low, priming dose of epinephrine. When mice with a partial deficiency of calstabin 2, which are asymptomatic at rest, undergo exercise stress testing, ventricular tachycardia or syncope develops, and most die during or shortly after exercise. Ventricular tachycardia could be induced in the mice with a partial deficiency of calstabin2 by administering an infusion of isoproterenol and subjecting them to electrophysiological programmed stimulation with overdrive pacing or with two coupled premature ventricular beats, but not after pretreatment with JTV519. Pretreatment with JTV519 prevented all arrhythmic events and deaths in the mice with a partial deficiency of calstabin2.
JTV519 significantly increases the affinity of calstabin2 for phosphorylated RyR2 (the phosphorylation of RyR2 normally decreases the affinity of RyR2 for calstabin2). Other drugs that increase the binding of calstabin2 to RyR2 and decrease the risk of arrhythmia, such as beta-blockers, do so by reducing the hyperphosphorylation of RyR2 commonly found in hyperadrenergic states and the failing human heart.3,4 Thus, whereas both JTV519 and beta-blockers modify RyR2 activity by enhancing calstabin2 binding, they act through different mechanisms and could act synergistically to improve clinical outcomes.
The study by Wehrens et al. opens a door for the treatment of CHF and the prevention of sudden death. Since it addresses the antiarrhythmic activity of JTV519 only in a genetically engineered calstabin2-knockout model, in which the primary myocardial lesion (calcium leakage) is diastolic and the drug requires intravenous delivery, future studies will need to address the antiarrhythmic activity of calstabin2 stabilizers in ischemic and nonischemic models of systolic dysfunction, in addition to the potency of orally delivered congeners. The idea that calstabin2 stabilizers may help to counter systolic dysfunction is supported by the finding that JTV519 improves hemodynamics in dogs with systolic heart failure induced by sustained, rapid, right ventricular pacing.5
An intriguing question is whether calstabin2 stabilizers can help prevent CHF or whether their efficacy is restricted to active CHF in which the downward spiral of calstabin2 dissociation from RyR2 has already been activated. Just as angiotensin-converting–enzyme inhibitors arose out of basic analyses of neurohormonal signaling mechanisms and revolutionized our approach to CHF, the use of calstabin2 stabilizers to control a mechanism central to the failing heart may someday be an essential weapon in our clinical arsenal.
Source Information
From the Molecular Cardiology Laboratory and Congestive Heart Failure Center, Greenberg Cardiology Division, Department of Medicine, Weill Medical College of Cornell University, New York.
References
Wehrens XH, Lehnart SE, Reiken SR, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. Science 2004;304:292-296.
Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001;103:196-200.
Reiken S, Gaburjakova M, Gaburjakova J, et al. Beta-adrenergic receptor blockers restore cardiac calcium release channel (ryanodine receptor) structure and function in heart failure. Circulation 2001;104:2843-2848.
Marx SO, Reiken S, Hisamatsu Y, et al. PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 2000;101:365-376.
Yano M, Kobayashi S, Kohno M, et al. FKBP12.6-mediated stabilization of calcium-release channel (ryanodine receptor) as a novel therapeutic strategy against heart failure. Circulation 2003;107:477-484.(Maryjane A. Farr, M.D., a)