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(Circulation. 2005;112:e367.)
© 2005 American Heart Association, Inc.

Correspondence

Letter Regarding Article by von Lewinski et al, "Insulin Causes [Ca²⁺]_i-Dependent and [Ca²⁺]_i-Independent Positive Inotropic Effects in Failing Human Myocardium"

Chih-Hsueng Hsu, MD; Cheng-I Lin, PhD; Jeng Wei, MD

National Defense Medical Center, Taipei, Taiwan, ROC bme03{at}mail.ndmctsgh.edu.tw

To the Editor:

We read with great interest the study by von Lewinski et al¹ reporting insulin-caused [Ca²⁺]_i-dependent and [Ca²⁺]_i-independent positive inotropic effects in failing human myocardium. Some aspects of this work deserve further comment.

The commercial insulin preparation used by the authors contains traces of preservative (m-cresol, 3-methylphenol) as a result of the manufacturing process. The maximal concentration of insulin (3 IU/L, equivalent to 20 nmol/L) used by the authors was significantly lower than concentrations used in previous studies.^2,3 von Lewinski et al¹ reported that the insulin-mediated positive inotropic effect is partially substrate-dependent. However, the authors did not mention that their observed insulin effects are contradictive of several previous studies.^2,3 Lee and Downing² reported that commercial insulin (1 IU/mL) induced a biphasic inotropic response to piglet moderator band. The initial negative effect was due to the preservative (0.2% phenol) present in the insulin solution. Moreover, Sethi et al³ found that the maximal positive response of insulin was not diminished by the absence of glucose or the presence of iodoacetate in the perfusion medium. In addition, the concentration of pyruvate (22.4 mmol/L) used in the study by von Lewinski et al¹ was too high and will affect the response of Na⁺-Ca²⁺ exchanger to insulin.

We have recently reported that insulin (Humulin R 100 IU/mL, Lilly) exerted pronounced biphasic inotropic effects in isolated failing human myocardium⁴ (0.5 Hz, 37°C, [Ca²⁺]_o 2.7 mmol/L). At low concentrations (10 to 1000 nmol/L), insulin increased contractility with maximum inotropy +29±6% at 100 nmol/L. The negative inotropy (–21±5% at 10 µmol/L) of high concentrations (1 µmol/L) was due to the preservative (0.25% m-cresol). Crystalline recombinant human insulin (Sigma) increased the contractile force in a dose-dependent manner, with a maximum increase of 45±11% at 1 µmol/L, and the negative inotropic response was absent. Maximal positive response to insulin was not reduced by the absence of glucose in the perfusion medium.

Hasenfuss et al¹ also applied a higher insulin concentration (10 IU/L), which might affect the experimental results in the perfusion medium in another study.⁵ How do the authors interpret their data in light of the above controversial results? Do they attribute this controversy to the different type of insulin used?

	Acknowledgments

 
The authors’ research on this topic received financial support from the National Science Council and Cheng-Hsin General Hospital, Taipei, Taiwan.

Disclosures

None.

	References

Top References Acknowledgments  References

 

1. von Lewinski D, Bruns S, Walther S, Kogler H, Pieske B. Insulin causes [Ca²⁺]_i-dependent and [Ca²⁺]_i-independent positive inotropic effects in failing human myocardium. Circulation. 2005; 111: 2588–2595.[Abstract/Free Full Text]
   
2. Lee JC, Downing SE. Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine. Am J Physiol. 1976; 230: 1360–1365.[Abstract/Free Full Text]
   
3. Sethi R, Rupp H, Naimark BJ, Barwinsky J, Beamish RE, Dhalla NS. Characteristics and mechanisms of tachyphylaxis of cardiac contractile response to insulin. Int J Cardiol. 1993; 38: 119–130.[Medline] [Order article via Infotrieve]
   
4. Hsu CH, Wei J, Chen YC, Yang SP, Tsai CS, Lin CI. Positive inotropic action of insulin in failing human myocardium Int J Cardiol. 2004; 97 (suppl 2): S24. Abstract.
   
5. Hasenfuss G, Maier LS, Hermann HP, Luers C, Hunlich M, Zeitz O, Janssen PM, Pieske B. Influence of pyruvate on contractile performance and Ca²⁺ cycling in isolated failing human myocardium. Circulation. 2002; 105: 194–199.[Abstract/Free Full Text]
   

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Response

Dirk von Lewinski, MD; Sebastian Bruns; Stefanie Walther; Harald Kögler, MD; Burkert Pieske, MD

Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Göttingen, Germany

We read with interest the letter by Hsu and colleagues. The authors point to potentially confounding effects of stabilizing agents of commercially available insulin on inotropy, as well as to differences between the functional effects of insulin in our recently published paper and previous reports.

The positive inotropic effect of insulin in failing human myocardium presented by Hsu, Lin, and Wei at concentrations 100 nmol/L fits well with the data presented in our report. The authors state that commonly used preservatives such as m-cresol and phenol might have negative inotropic effects as described for phenol¹ and as shown for m-cresol in their own data. The insulin we used² (Insuman Rapid 100 IU/mL, Hoechst Marion Russell, now Aventis) contains 2.7 mg of m-Cresol per milliliter (200 nmol/L in our final solution) but no phenol, which is only used to stabilize longer-acting insulin suspensions. Negative inotropic effects of preservatives such as m-cresol and phenol were observed previously at much higher concentrations than we used in our study (330-fold higher in the study by Lee et al, and 50- to 500-fold higher in the study by Hsu, Lin, and Wei). We did not observe the preservative-associated initial negative inotropic effects at insulin concentrations 10 IU/L in our study, and therefore, we do not assume that m-cresol at low concentrations (<100 µg/L in our Tyrode’s solution) reduced significantly the observed functional effect of insulin

Furthermore, functional effects of insulin vary between species. Using identical experimental conditions, we have observed negative inotropic effects at 5, 10, and 20 IU/L insulin in rabbit trabeculae. Force declined by 9±3%, 15±4%, and 14±2% (all P<0.05), respectively. Similarly, under identical experimental conditions, phenol mediated negative inotropic effects only in piglet moderator band but not in cat and kitten papillary muscle, which indicates species differences for functional effects of preservatives.¹

Because the different insulins used by Hsu, Lin, and Wei and us have comparable positive inotropic effects in human myocardium, we attribute controversies about direction and extent of inotropic effects of insulin in cardiac muscle to species differences and/or different types and concentrations of preservatives and not to the type of insulin used in published reports.

	Acknowledgments

Top References Acknowledgments  References

 
Disclosures

None.

	References

Top References Acknowledgments  References

 

1. Lee JC, Downing SE. Effects of insulin on cardiac muscle contraction and responsiveness to norepinephrine. Am J Physiol. 1976; 230: 1360–1365.[Abstract/Free Full Text]
   
2. von Lewinski D, Bruns S, Walther S, Kogler H, Pieske B. Insulin causes [Ca²⁺]_i-dependent and [Ca²⁺]_i-independent positive inotropic effects in failing human myocardium. Circulation. 2005; 111: 2588–2595.[Abstract/Free Full Text]
   

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