Istaroxime, a Stimulator of Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Isoform 2a Activity, as a Novel Therapeutic Approach to Heart Failure

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Interventions involving calcium cycling may represent a promising approach to heart failure (HF) therapy because calcium handling is known to be deranged in human and experimental HF. Istaroxime is a sodium-potassium adenosine triphosphatase (ATPase) inhibitor with the unique property of increasing sarcoplasmic reticulum calcium ATPase (SERCA) isoform 2a (SERCA2a) activity. Because this was demonstrated in normal experimental models, we investigated whether istaroxime is able to improve global cardiac function and stimulate SERCA in failing hearts. In guinea pigs with 3-month aortic banding (AoB), echocardiographic results showed that istaroxime intravenous infusion (0.11 mg/kg per min) significantly increased both indices of contraction and relaxation (fractional shortening, +18 ± 3.7%; aortic flow rate, +19 ± 2.9%; peak myocardial systolic velocity, +36 ± 7%; circumferential fiber shortening, +24 ± 4.1%; peak atrial flow velocity, +69 ± 8.6%; isovolumic relaxation time, +19 ± 6.9%; and peak myocardial early diastolic velocity, +42 ± 12%). In left ventricular sarcoplasmic reticulum microsomes from AoB animals, 100 nmol/L istaroxime normalized the depressed (−32%) SERCA2a maximum velocity and increased SERCA activity (+17%). In muscle strips from hearts from patients undergoing cardiac transplantation, istaroxime (0.1–1.0 μmol/L) increased (in a concentration-dependent manner) developed tension, the maximum and minimum first derivative of tension, and absolute velocity of contraction, while stimulating SERCA activity in sarcoplasmic reticulum microsomes at physiologic free calcium concentrations. In conclusion, istaroxime is presently the only available compound that stimulates SERCA2a activity and produces a luso-inotropic effect in HF.

Section snippets

Calcium Cycling in Heart Failure

Calcium fluxes regulate both contraction and relaxation, potentially increasing oxygen consumption and thus contributing to impaired tissue viability. Myocytes from patients with HF show smaller calcium transients that also decrease more slowly than normal,5, 7 indicating a decrease in the sarcoplasmic reticulum calcium content and in sarcoplasmic reticulum calcium adenosine triphosphatase (ATPase) (SERCA) isoform 2a (SERCA2a) pump activity.

The reduced sarcoplasmic reticulum calcium content in

Istaroxime

Istaroxime is an inhibitor of sodium-potassium ATPase that exhibits the unique property of increasing SERCA2a activity. This has been demonstrated in sarcoplasmic reticulum vesicles from normal guinea pigs, where istaroxime increased SERCA2a affinity for calcium in the calcium physiologic concentration range. Such an effect presumably favors sarcoplasmic reticulum calcium reloading. In fact, the functional correlate of SERCA2a stimulation in isolated guinea pig myocytes was a higher magnitude

In vivo HF model

Guinea pigs were used for the evaluation of cardiac function or SERCA2a activity 12 weeks after banding of the ascending aorta (AoB) performed under ketamine-xylazine, 100 mg/kg intraperitoneally.

For cardiac function, a full transthoracic echocardiographic and Doppler evaluation (Sequoia 512 equipped with a 13-MHz probe; Acuson, Mountain View, CA) under urethane (1.5 g/kg intraperitoneally) anesthesia was performed before and during intravenous infusion of 0.11 mg/kg per min istaroxime or

Results

AoB induced significant hypertrophy of both the intraventricular septum and posterior wall, with an increase in LV mass (1.512 ± 55 mg, 2.220 ± 130 mg, and 2.111 ± 110 mg, in sham, AoB-S, and AoB-I groups, respectively; p <0.005). LVEDD increased in AoB groups to near statistical significance (Table 1). In AoB animals, saline solution infusion significantly increased the LVESD, whereas istaroxime reduced it (Table 1). Therefore, fractional shortening decreased by 7% in the AoB-S group and

Discussion

We have recently reported that the lusitropic properties displayed by istaroxime in normal animals27 may be attributed to its unique ability to stimulate SERCA2a activity.26 Our aim in this study was to extend investigations to animals with cardiac hypertrophy and failure. Because we had characterized the interaction of istaroxime with SERCA2a in guinea pigs, we used a model of guinea pig HF. The pressure overload model described here shows clear evidence of LV hypertrophy and mild cardiac

Conclusion

At the present state of knowledge, istaroxime is the only available compound that stimulates SERCA2a activity and produces a luso-inotropic effect in HF.

Acknowledgment

We are indebted to Dr. P. M. Janssen for teaching us the methodology to study in vitro human trabeculae. We acknowledge the Consiglio Nazionale delle Ricerche–CNR, Institute of Clinical Physiology and the Cardiosurgery Division at the Niguarda Ca’ Granda Hospital for providing us with the human cardiac samples (Ethical Committee Approval No. 3755/99).

References (33)

  • 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)
  • C.H. Davies et al.

    Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure

    Circulation

    (1995)
  • S. Reiken et al.

    Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure

    Circulation

    (2003)
  • S.E. Lehnart et al.

    Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak

    Circulation

    (2004)
  • D.M. Bers
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