Targeting SERCA2a as an innovative approach to the therapy of congestive heart failure

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Summary

CHF prevalence is continuously increasing worldwide and maintains one of the poorest prognoses of any major disease. Abundant evidence points to derangement of Ca2+ cycling as the primary biochemical mark of the failing myocyte. Istaroxime is a novel compound with a dual mechanism of action: inhibition of Na+, K+-ATPase and stimulation of SERCA2a. The increase in cytoplasmic Ca2+ due to Na+, K+-ATPase inhibition together with greater sarcoplasmic reticulum reloading result in both increased inotropy and lusitropy. This effect is seen in normal and failing in vitro and in vivo models. Istaroxime improvement of the contraction–relaxation cycle constitutes a novel therapeutic approach to the treatment of heart failure.

Introduction

Congestive heart failure (CHF) affects approximately 2.3% of the total US population [1], and continues to increase globally due to an aging population and improved secondary prevention of acute myocardial infarction and hypertension. In 2003 in the United States, more than one million patients were discharged with a diagnosis of primary heart failure, the incidence being about 10/1000 after age 65 [1].

CHF is a severe disease and has one of the poorest prognoses of any major disease and a mortality rate comparable to that of many common types of cancer [2]. The one-year mortality rate for severe CHF approaches 50%, and even with recent improvements in treatment, this remains a disappointing prognosis.

Two pathological features underlie most of the clinical findings in CHF, and the majority of patients show alterations consistent with both:

  • an inotropic abnormality resulting in diminished systolic emptying (systolic dysfunction);

  • a compliance abnormality in which the ability of the ventricles to accept blood is impaired (diastolic dysfunction).

Common causes of systolic failure are coronary artery disease, hypertension and idiopathic or toxic dilated cardiomyopathy. Diastolic dysfunction is mainly due to hypertension and hypertrophic cardiomyopathy [3].

The acute decompensation episodes occurring during CHF constitute a definite pathophysiological entity (ADHF) [4]. The succession of ADHF episodes results in a progressive worsening of cardiac function and poor general conditions mainly characterized by: mitral regurgitation, increase in wall stress with consequent subendocardial ischemia and myocyte necrosis, activation of the neurohormonal pathway responsible for vasoconstriction, tachycardia and fluid retention, and decrease in cardiac output (CO) with consequent hypotension and reduced organ perfusion [3].

In this scenario, the available therapeutic approaches mainly address reducing hemodynamics deterioration, improving both systolic and diastolic function, lowering neurohormonal activation, and facilitating fluid excretion. To this end, CHF treatment benefits from the use of a wide variety of therapeutic classes: ACE inhibitors, β blockers, diuretics, inotropes, BNP-like agents, Ca2+ sensitizers [5]. In particular, ADHF, the ultimate trigger of the progressive deterioration of heart function in CHF, is principally treated by the so-called preload and afterload reducers for patient’s relief of symptoms and life-saving [6]. The immediate management of ADHF patients often requires inotropic support. There is evidence that some drugs employed in AHF to improve hemodynamics, namely dobutamine and milrinone, may adversely affect long-term outcome [7] As approximately 60% of patients admitted with ADHF have coronary artery disease [4], a sizeable proportion of them will have ischemic and/or hibernating myocardium. It is thus conceivable that an inadequate O2 supply to this tissue in the presence of inotropic stimulation and vasodilator therapy is detrimental to tissue viability, affecting coronary blood flow particularly in those patients experiencing a marked drop in blood pressure. Indirect evidence for the occurrence of myocyte damage comes from troponin plasma concentrations, which negatively correlate with the prognosis, corroborated by a recent study showing raising troponin levels during ADHF hospitalization in concomitance with short-term negative events (worsening CHF and death) [8]. Thus, myocardial injury should undoubtedly be avoided [8].

Given the complex etiology of heart failure, it emerges that, despite available therapy, there is no effective, safe, oral chronic cardiotonic treatment for systolic and diastolic dysfunction in CHF, and safe and effective positive inotropes and lusitropes are urgently needed.

Since cardiac contractility and relaxation are compromised in CHF, a logical therapeutic approach should improve the efficiency of the contraction–relaxation cycle, which is heavily regulated by Ca2+; in fact, ample evidence for derangement of Ca2+ handling in human and experimental CHF points to Ca2+ as the unifying biochemical abnormality in CHF [9], [10]. Therefore, the objective is to identify appropriate molecular target(s) where pharmacological interventions may result in inotropic, and particularly lusitropic, activity.

Section snippets

Ca2+cycling in CHF

The Ca2+ cycle is a definite regulator of myocyte contraction and relaxation [11]. During a normal cardiac cycle, membrane depolarization leads to Ca2+ entry into the cell via l-type Ca2+ channel (Fig. 1a). The entry of Ca2+, in close proximity to the sarcoplasmic reticulum (SR), triggers a calcium-dependent calcium release through the SR ryanodine-sensitive receptors (RyRs); Ca2+ diffuses to the myofilaments and activates calcium-sensitive proteins leading to myofibrillar contraction. The

Hypotheses

Although ACE inhibitors and β blockers effectively reduce the frequency of hospitalization and improve survival rate in CHF patients, the medical need for an effective and safe treatment of CHF is still unmet [23]. Interest in an innovative approach to CHF treatment is highlighted by ongoing investigations of several classes of compounds, i.e., natriuretic peptide analogues, Ca2+ sensitizers, endothelin inhibitors, vasopressin antagonists, adenosine receptor antagonists, inhibitors of immune

Istaroxime

Istaroxime is a Na+, K+-ATPase inhibitor that exhibits the unique property of increasing SERCA2a activity (Fig. 1) [26], [27], [28]. This was demonstrated in SR vesicles from normal guinea pigs, where Istaroxime increased SERCA2a affinity for Ca2+, in a physiological Ca2+ concentration range (100–200 nM) [26]. Recently, the efficacy of Istaroxime in stimulating SERCA2a activity was also shown in animal and human failing heart preparations [28]. Notably, in these preparations where SERCA2a Vmax

Future developments

The success of the pharmacological strategy to develop lusi-inotropic agents able to improve SERCA2a function for treatment of ADHF has stimulated the search for new compounds, effective in oral chronic treatment of CHF. New molecules, still characterized by high affinity for SERCA2a but with a longer half-life and lower metabolic transformation than Istraroxime, are currently under selection.

In conclusion, the strong rationale for regarding SERCA2a function as a novel therapeutic target for

References (37)

  • M. Bayram et al.

    Reassessment of dobutamine, dopamine, and milrinone in the management of acute heart failure syndromes

    Am J Cardiol

    (2005)
  • M. Gheorghiade et al.

    The pilot randomized study of Nesiritide versus dobutamine in heart failure (PRESERVED-HF)

    Am J Cardiol

    (2005)
  • M. Yano et al.

    Altered intracellular Ca2+ handling in heart failure

    J Clin Invest

    (2005)
  • D.M. Bers

    Excitation–contraction coupling and cardiac contractile force

    (2001)
  • M. Meyer et al.

    Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy

    Circulation

    (1995)
  • B. O’Rourke et al.

    Mechanisms of altered excitation–contraction coupling in canine tachycardia-induced heart failure, I: experimental studies

    Circ Res

    (1999)
  • S.M. Pogwizd et al.

    Upregulation of Na+/Ca2+ exchanger expression and function in an arrhythmogenic rabbit model of heart failure

    Circ Res

    (1999)
  • G. Hasenfuss et al.

    Relationship between Na+–Ca2+-exchanger protein levels and diastolic function of failing human myocardium

    Circulation

    (1999)
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