Pharmacology of New Agents for Acute Heart Failure Syndromes

doi:10.1016/j.amjcard.2005.07.023

The American Journal of Cardiology

Volume 96, Issue 6, Supplement, 19 September 2005, Pages 68-73

https://doi.org/10.1016/j.amjcard.2005.07.023 Get rights and content

Current therapies for acute heart failure syndromes (AHFS) target hemodynamics by decreasing congestion or increasing myocardial contraction. Several new agents for AHFS use novel mechanisms of action that focus on new treatment targets, such as those providing anti-ischemic and antistunning effects, blocking vasopressin receptors, or blocking endothelin-1 receptors. For example, levosimendan acts as a calcium sensitizer and adenosine triphosphate–dependent potassium (K_ATP) channel opener that increases contraction, causes vasodilation, and provides cardioprotective effects. This is accomplished by its dual mechanism of action. Levosimendan binds to cardiac troponin C, thereby enhancing calcium myofilament responsiveness and increasing myocardial contraction without increasing intracellular calcium levels. Thus, contraction is increased with no significant increase in myocardial oxygen consumption. The opening of K_ATP channels by levosimendan causes vasodilation and exerts anti-ischemic and antistunning effects on the myocardium. Other new agents target neurohormonal pathways. Tezosentan is an antagonist of endothelin-1 receptors A and B. By inhibiting endothelin-1 receptors, tezosentan may counteract the activities of endothelin-1, which include vasoconstriction, proarrhythmic activities, potentiation of other neurohormones, and mediation of increased vascular permeability. Tolvaptan is a vasopressin V₂–receptor antagonist that functions as an aquaretic (ie, it increases urine volume and serum sodium with little or no sodium loss). Therefore, by using novel mechanisms of action, these agents may provide new opportunities for helping patients with AHFS.

Section snippets

Levosimendan

Levosimendan is a novel compound for the treatment of AHFS. This new agent is clearly distinguishable from conventional therapies for AHFS because of its mechanisms of action and its clinical attributes. Levosimendan is currently being used to treat AHFS patients in 38 countries, including several European countries, and is undergoing phase 3 clinical studies in the United States and Europe.1, 2 In addition to improving hemodynamics, levosimendan has also been shown to improve survival in

Tezosentan

The success of the neurohormonal hypothesis in developing new therapies for chronic HF led to the application of this same theory to AHFS. Endothelin, a neurohormone produced predominantly by vascular tissue, was discovered <20 years ago⁶⁵ and was rapidly demonstrated to not only be among the most potent known vasoconstrictors but also to mediate pathologic ventricular and vascular remodeling.⁶⁶ The effects of endothelin are mediated by 2 receptor subtypes: endothelin-A receptors, which are

Tolvaptan

Tolvaptan is a vasopressin receptor inhibitor that functions as an aquaretic agent and is undergoing phase 3 clinical studies. This agent has been shown to decrease body weight significantly by increasing urine output in patients with AHFS and may therefore serve to help manage systemic congestion.72, 73

Conclusion

The growth in our knowledge of the pathophysiology of AHFS has opened up possibilities for new methods of intervention in this growing healthcare problem. Elevated levels of neurohormones, such as endothelin-1 and vasopressin, contribute to the progression of HF and may serve as good targets in treating AHFS. For this reason, agents that target neurohormonal activation may play a valuable role alongside other treatments for AHFS. Myocardial injury is likely to play a critical role in the

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Cardiogenic shock is characterized by a decrease in myocardial contractility, and presents a high mortality rate. Inotropic and vasopressor agents have been recommended and used for several years in the treatment of patients in shock, but they remain controversial. Despite its beneficial effect on myocardial contractility, the side effects of inotropic therapy (arrhythmias and increased myocardial oxygen consumption) may be associated with increased mortality.
The pharmacodynamics of different inotropic agents suggest benefits in specific situations, but these differences have not been reflected in reduced mortality in most studies, making it difficult to formulate recommendations.
This review integrates data from different studies on the use of inotropes and vasopressors in patients with cardiogenic shock, proposing a therapeutic scheme for the pharmacological treatment of patients in cardiogenic shock according to the patient's hemodynamic profile.
Inotropes
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Therefore, such drugs have the theoretical advantage of driving contractile state without increasing cAMP or calcium itself, both of which have adverse effects. It appears that levosimendan's ability to enhance calcium responsiveness of myofilaments potentiates cross-bridge formation, thereby augmenting contractility and enhancing relaxation (59). Levosimendan causes a rapid dose-dependent improvement in the deranged hemodynamic profile of patients with severe heart failure (60).
Inotropes have been fundamental to resuscitation of acute cardiogenic shock for decades. Heart failure and cardiogenic shock, in severe cases, are syndromes characterized in many patients by a reduction in myocardial contractile force. While inotropes successfully increase cardiac output, their use has been plagued by excessive mortality due to increased tachycardia and myocardial oxygen consumption leading to arrhythmia and myocardial ischemia. There is a pressing need for new inotropic agents that avoid these harmful effects. This review describes the mechanism of action and the clinical utility of some of the older inotropic agents, which are still commonly used, and provides an update for physicians on the development of newer inotropic drugs. The field is rapidly changing, and it is likely that new agents will be designed that improve systolic performance without necessarily increasing the myocardial oxygen consumption.
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This poor prognosis is thought to be associated with the elevated intracellular Ca2+ level. Recently, calcium sensitizers that increase myofilament tensions at a given intracellular Ca2+ level were suggested as a promising class of inotropic agents [52–54]. Our data show that the inhibition of PKCζ could be a novel and safe strategy to increase cardiac contractility.
Protein kinase C (PKC)-interacting cousin of thioredoxin (PICOT) has distinct anti-hypertrophic and inotropic functions. We have previously shown that PICOT exerts its anti-hypertrophic effect by inhibiting calcineurin-NFAT signaling through its C-terminal glutaredoxin domain. However, the mechanism underlying the inotropic effect of PICOT is unknown. The results of protein pull-down experiments showed that PICOT directly binds to the catalytic domain of PKCζ through its N-terminal thioredoxin-like domain. Purified PICOT protein inhibited the kinase activity of PKCζ in vitro, which indicated that PICOT is an endogenous inhibitor of PKCζ. The inhibition of PKCζ activity with a PKCζ-specific pseudosubstrate peptide inhibitor was sufficient to increase the cardiac contractility in vitro and ex vivo. Overexpression of PICOT or inhibition of PKCζ activity down-regulated PKCα activity, which led to the elevation of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA) 2a activity, concomitant with the increased phosphorylation of phospholamban (PLB). Overexpression of PICOT or inhibition of PKCζ activity also down-regulated protein phosphatase (PP) 2A activity, which subsequently resulted in the increased phosphorylation of troponin (Tn) I and T, key myofilament proteins associated with the regulation of contractility. PICOT appeared to inhibit PP2A activity through the disruption of the functional PKCζ/PP2A complex. In contrast to the overexpression of PICOT or inhibition of PKCζ, reduced PICOT expression resulted in up-regulation of PKCα and PP2A activities, followed by decreased phosphorylation of PLB, and TnI and T, respectively, supporting the physiological relevance of these events. Transgene- or adeno-associated virus (AAV)-mediated overexpression of PICOT restored the impaired contractility and prevented further morphological and functional deterioration of the failing hearts. Taken together, the results of the present study suggest that PICOT exerts its inotropic effect by negatively regulating PKCα and PP2A activities through the inhibition of PKCζ activity. This finding provides a novel insight into the regulation of cardiac contractility.
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Pharmacology of New Agents for Acute Heart Failure Syndromes

Section snippets

Levosimendan

Tezosentan

Tolvaptan

Conclusion

J Card Fail

J Am Coll Cardiol

Lancet

Eur J Pharmacol

Eur J Pharmacol

Eur J Pharmacol

J Biol Chem

J Mol Cell Cardiol

J Mol Cell Cardiol

J Biol Chem

J Mol Cell Cardiol

Eur J Pharmacol

J Am Coll Cardiol

J Mol Cell Cardiol

Eur J Pharmacol

Biochem Pharmacol

Eur J Pharmacol

Biochim Biophys Acta

J Card Fail

Eur J Pharm Sci

Eur J Pharm Sci

Biochem Biophys Res Commun

J Am Coll Cardiol

Am J Med

J Biol Chem

Study design of a mortality trial with intravenous levosimendan (the SURVIVE study) in patients with acutely decompensated heart failure

Program and abstracts of the 8th Annual Scientific Meeting of the Heart Failure Society of America

Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure

Circulation

Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarctiona randomized, placebo-controlled, double-blind study (RUSSLAN)

Eur Heart J

Troponin and tropomyosinproteins that switch on and tune in the activity of cardiac myofilaments

Circ Res

Effects of levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart

Circ Res

Troponin C–mediated calcium sensitization induced by levosimendan does not impair relaxation

J Cardiovasc Pharmacol

The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan

Cardiovasc Res

Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium

Circulation

Beneficial effects of the Ca2+ sensitizer levosimendan in human myocardium

Am J Physiol Heart Circ Physiol

Mechanisms of action of calcium-sensitizing drugs

J Cardiovasc Pharmacol

Levosimendan enhances left ventricular systolic and diastolic function in conscious dogs with pacing-induced cardiomyopathy

J Cardiovasc Pharmacol

Levosimendan improves left ventricular systolic and diastolic performance at rest and during exercise after heart failure

Am J Physiol Heart Circ Physiol

Clinical practicediastolic heart failure

N Engl J Med

Cardiac responses to calcium sensitizers and isoproterenol in intact guinea pig heartseffects on cyclic AMP levels, protein phosphorylation, myoplasmic calcium concentration, and left ventricular function

Ann N Y Acad Sci

Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics

J Cardiovasc Pharmacol

Myocardial efficiency during levosimendan infusion in congestive heart failure

Clin Pharmacol Ther

Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow, and myocardial substrate utilization early after coronary artery bypass grafting

Eur Heart J

Effects of levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca²⁺ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart

Beneficial effects of the Ca²⁺ sensitizer levosimendan in human myocardium